CN103582630B - Enkephalinase inhibitor - Google Patents

Enkephalinase inhibitor Download PDF

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Publication number
CN103582630B
CN103582630B CN201280027257.5A CN201280027257A CN103582630B CN 103582630 B CN103582630 B CN 103582630B CN 201280027257 A CN201280027257 A CN 201280027257A CN 103582630 B CN103582630 B CN 103582630B
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compound
alkyl
acid
halogen
alkylidene
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CN103582630A (en
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梅丽莎·弗勒里
罗兰·根德龙
亚当·D·休斯
简·施密特
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Theravance Biopharma R&D IP LLC
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Theravance Biopharma R&D IP LLC
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Abstract

In an aspect, the present invention relates to the compound with lower formula (I):Wherein R1、R2、R3、X、R4、R5And R6It is to be defined as in the description, or its pharmaceutically acceptable salt.These compounds have enkephalinase inhibitory activity.In another aspect, the present invention relates to comprise the medical composition of described compound；The method using described compound；And prepare method and the intermedium of described compound.

Description

Enkephalinase inhibitor
Technical field
The present invention relates to the compounds with enkephalinase (neprilysin) inhibitory activity.The invention still further relates to bag Medical composition containing these compounds, the method preparing these compounds and intermedium and use these compounds for treating such as The method of the disease of hypertension, heart failure, pulmonary hypertension and nephropathy.
Background technology
Enkephalinase (neutral endopeptidase, EC 3.4.24.11) (NEP) is that one is found in many organs and tissue, including Interior epithelium in brain, kidney, lung, gastrointestinal tract, heart and peripheral blood vessel structure combines Zn2+Metallopeptidase.NEP makes many endogenous peptides Degraded and inactivation, described peptide such as enkephalin (enkephalin), circulation Kallidin I (circulating bradykinin), blood vessel Angiotensin Converting Enzyme peptide (angiotensin peptide) and natriuretic peptide (natriuretic peptide), wherein natriuretic peptide has several Effect, including such as vasodilation and natruresis/diuresis and suppression megalocardia and myocardial fibrosis.Therefore, NEP is at blood pressure Constant and cardiovascular health plays an important role.
Such as Sai Aofen (thiorphan), candoxatril (candoxatril) and the NEP of candoxatrilat (candoxatrilat) Inhibitor is studied as potential therapeutic agent.It is known that suppression NEP and Angiotensin-I Converting enzyme (ACE) both changes Compound, and it includes omapatrilat (omapatrilat), lattice handkerchief QULA (gempatrilat) and sampatrilat (sampatrilat).Hereafter a compounds is referred to as vasopeptidase (vasopeptidase) inhibitor, is described in and spreads out you (Robl) et al., in (1999) iatrotechnics patent expert opinion (Exp.Opin.Ther.Patents) 9 (12): 1665-1677.
Summary of the invention
The present invention provides it has been found that the compounds of enkephalinase (NEP) enzyme inhibition activity.It is therefore contemplated that this Bright compound can be advantageously suitable as treatment such as hypertension and the therapeutic agent of the condition of illness of heart failure.
One aspect of the present invention relates to compound of formula I:
Wherein:
R1For-OR10Or-NR60R70；
R2For H or-OR20；
R3It is selected from H, Cl, F ,-CH3With-CF3；
X is-C1-10Heteroaryl or part unsaturation-C2-12Heterocycle, its restrictive condition is that X is not for pyrazoles；
R4Do not exist or selected from H；Halogen；-C0-5Alkylidene-OH；-NH2；-C1-6Alkyl；-CF3；-C3-7Cycloalkyl；- C0-2Alkylidene-O-C1-6Alkyl；-C(O)R40；-C0-1Alkylidene-C (O) OR41；-C(O)NR42R43；-NHC(O)R44；=O；- NO2；Furan；Pyrazine；Naphthalene；Pyridine；Optionally through methyl substituted pyrazoles；Optionally through methyl substituted thiophene；With optionally through being selected from Halogen ,-OH ,-CF3、-OCH3、-NHC(O)CH3With phenyl substituted phenyl of group；And R4In the presence of to be connected to carbon former Son；And when X is pyridazine, pyrazine or pyridine, R4Can be also through-C (O) OR41Substituted phenyl；
R5Do not exist or selected from H；-C1-6Alkyl；-C0-3Alkylidene-OH；-[(CH2)2O]1-3CH3；-C1-3Alkylidene-C (O)OR50；-CH2-C(O)NR51R52；Optionally through the substituted-C of halogen0-2Alkylene-pyridine；Optionally through methyl substituted-CH2-different Azoles；Optionally through-O-C1-6Substituted-the CH of alkyl2-pyrimidine；-C2Alkylen-phenyl；
And R5In the presence of be connected to nitrogen-atoms；
R6Do not exist or selected from H, halogen ,-OH ,-C1-6Alkyl and-O-C1-6Alkyl；And R6In the presence of to be connected to carbon former Son；
R10、R41And R50Independently selected from H ,-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylidene-C1-9Heteroaryl Base ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、-C1-6Alkylidene- C(O)R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
R13It is selected from-C1-6Alkyl ,-O-C1-6Alkyl ,-C3-7Cycloalkyl ,-O-C3-7Cycloalkyl, phenyl ,-O-phenyl ,- NR14R15With-CH (NH2)CH2COOCH3；R14And R15Independently selected from H ,-C1-6Alkyl and benzyl, or R14And R15Shape together One-tenth-(CH2)3-6-、-C(O)-(CH2)3-or-(CH2)2O(CH2)2-；R16For-C1-6Alkyl or-C0-6Alkylidene-C6-10Aryl；R17 It is selected from-O-C1-6Alkyl ,-O-benzyl and-NR14R15；
R20For H or together with R10Formation-CR together21R22-or together with R60Formation-C (O) together-；Wherein R21And R22Independently Selected from H ,-C1-6Alkyl and-O-C3-7Cycloalkyl, or R21And R22Formation=O together；
R40For H or-C1-6Alkyl；
R42、R43、R51And R52Independently selected from H ,-C1-6Alkyl ,-CH2COOH、-(CH2)2OH、-(CH2)2OCH3、- (CH2)2SO2NH2、-(CH2)2N(CH3)2、-C3-7Cycloalkyl and-(CH2)2-imidazoles；Or R42And R43Or R52And R53Formed full together With or part unsaturation-C3-5Heterocycle, it is optionally through-OH ,-COOR41Or-CONH2Replace and in described ring, optionally contain aerobic Atom；
R44It is selected from-C1-6Alkyl；-C0-1Alkylidene-O-C1-6Alkyl；Optionally through halogen or-OCH3Substituted phenyl；With- C1-9Heteroaryl；And
R53、R54、R55、R56And R57Independently selected from H, halogen ,-C1-6Alkyl ,-O-C1-6Alkyl and-S-C1-6Alkyl, its In each-C1-6Alkyl optionally replaces through 1 to 5 fluorine atoms；
R60It is selected from H ,-OH ,-OC (O) R61、-CH2COOH ,-O-benzyl, pyridine radicals and-OC (S) NR62R63；Wherein R61 It is selected from H ,-C1-6Alkyl ,-C6-10Aryl ,-OCH2-C6-10Aryl ,-CH2O-C6-10Aryl and-NR62R63；R62And R63Independently For H or-C1-4Alkyl；
R70It is selected from H ,-C1-6Alkyl and-C (O) R71；R71It is selected from H ,-C1-6Alkyl ,-C3-7Cycloalkyl ,-C6-10Aryl With-C1-9Heteroaryl；
Or its pharmaceutically acceptable salt.
Another aspect of the present invention relates to the medicinal combination comprising pharmaceutically acceptable supporting agent and the compounds of this invention Thing.These compositionss optionally contain other therapeutic agent.Therefore, in a still further aspect thereof, medical composition comprises The compounds of this invention, one or more second therapeutic agents and pharmaceutically acceptable supporting agent as the first therapeutic agent. Another aspect of the present invention relates to the combination of activating agent, and it comprises the compounds of this invention and the second therapeutic agent.The compounds of this invention Can be together with other medicament or separate allotment.When separately allocating, pharmaceutically acceptable supporting agent can be together with other medicament It is included.Therefore, another aspect of the present invention relates to the combination of medical composition, and described combination comprises: comprise the present invention Compound and the first medical composition of the first pharmaceutically acceptable supporting agent；With comprise the second therapeutic agent and the second medicine and pharmacology Second medical composition of upper acceptable supporting agent.In another aspect, the present invention relates to the examination containing these medical compositions Agent box, wherein the first and second medical compositions are medical composition out of the ordinary.
The compounds of this invention has a NEP enzyme inhibition activity, and it is anticipated that it is useful as treatment suffers from by suppression NEP enzyme Or the therapeutic agent of the patient of the disease treated by increasing its peptide substrates content or disease.Therefore, of the present invention Aspect relates to a kind for the treatment of and suffers from the method for the patient of the disease treated or disease by suppression NEP enzyme, its comprise to The compounds of this invention of patient's administration therapeutically effective amount.Another aspect of the present invention relates to one and treats hypertension, heart failure Or the method for nephropathy, it comprises the compounds of this invention to patient's administration therapeutically effective amount.Another aspect of the present invention relates to one Planting the method suppressing the NEP enzyme in mammal, it comprises the chemical combination of the present invention to described mammal administration NEP enzyme level amount Thing.
Because the compounds of this invention has NEP inhibitory activity, it is also suitable makees research tool.Therefore, the present invention One aspect relates to a kind of using the compounds of this invention as the method for research tool, and described method comprises use chemical combination of the present invention Thing carries out bioanalysis.The compounds of this invention can be additionally used in the compound that assessment is new.Therefore, another aspect of the present invention relates to one The method of assessment test compound kind in bioanalysis, it comprises: (a) carries out bioanalysis to provide the with test compound One assay value；B () carries out described bioanalysis to provide the second assay value with the compounds of this invention；Wherein step (a) is in step Suddenly before (b), afterwards or carry out with step (b) simultaneously；(c) will be from described first assay value of step (a) and from step Suddenly described second assay value of (b) compares.Exemplary bio analysis includes NEP enzyme level analysis.The opposing party of the present invention Face relates to a kind of research and comprises the biosystem of NEP enzyme or the method for sample, and described method comprises: (a) makes described biosystem Or sample contacts with the compounds of this invention；(b) measure by described compound cause to described biosystem or the shadow of sample Ring.
Another aspect of the present invention relates to method and the intermedium being applicable to prepare the compounds of this invention.Therefore, the present invention Another aspect a kind of relate to formula I method, it comprises the steps of (a) makes compound 1 even with compound 2 Close:
B () makes compound 1 and compound 2a coupling to form compound 3:
Wherein L is leaving group, such as halogen (such as bromine) or triflate (such as-OSO2CF3), and make compound 3 With the 4,4,5,5-tetramethyl-2-phenyl being optionally substituted-[1,3,2] dioxy boron pentane:
The coupling reaction of palladium chtalyst is reacted；Or (c) make compound 2b with the 4,4,5,5-tetramethyl being optionally substituted- 2-phenyl-[1,3,2] dioxy boron pentane reaction is to form compound 4 in the coupling reaction of palladium chtalyst:
Wherein L is leaving group, and P1For selected from methyl, ethyl, the tert-butyl group, benzyl, to mehtoxybenzyl, 9-fluorenyl The carboxyl-protecting group of methyl, TMS, t-butyldimethylsilyi and benzhydryl, and make compound 4 and chemical combination Thing 1 coupling；And (d) optionally makes the product removal protection group of step (a) or (b) or (c) with compound of formula I or its doctor Pharmaceutically acceptable salt；Wherein R1、R2、R3、X、R4、R5And R6It is as defined for Formulas I.Another aspect of the present invention relates to The method of the pharmaceutically acceptable salt of a kind of formula I, it comprises makes in free acid or the Formulas I of free alkali form Compound contacts with pharmaceutically acceptable alkali or acid.In other side, the present invention relates to by as herein described any The novel intermedium used in product prepared by method and described method.In one aspect of the invention, novel intermedium There is Formula II as defined herein.
Another aspect of the present invention relates to compound of formula I or the purposes of its pharmaceutically acceptable salt, and it is used for manufacturing Medicament, is particularly useful for manufacturing and is applicable to treat hypertension, heart failure or the medicament of nephropathy.Another aspect of the present invention relates to this Invention compound is for suppressing the purposes of the NEP enzyme in mammal.Another aspect of the present invention relates to the compounds of this invention and makees Purposes for research tool.The other side of the present invention disclosed herein and embodiment.
Accompanying drawing explanation
Detailed description of the invention
Definition
When describing the compound of the present invention, compositions, method and technique, unless otherwise instructed, otherwise following term has There is following meanings.It addition, unless the other clear stipulaties of context used, the most as used herein, singulative " " and " institute State " include corresponding plural form.Term " comprises ", " including " and " having " is intended to inclusive and means there may be and removes Other key element beyond listed elements.Unless otherwise instructed, the most used herein it is expressed as dosis refracta, character, such as molecule All numerical value of amount, reaction condition etc. are understood to the most all be modified by term " about ".Therefore, described herein The desired properties that reached out for by the visual present invention of numerical value and the approximation that changes.At least, and be not intended to doctrine of equivalents The application of (doctrine of equivalents) is limited to the scope of claims, and each numerical value should be according at least to being reported Significant digits and by application the typically technology of rounding off explain.
Term " alkyl " means can be the monovalent saturated hydrocarbon group of straight chain or branched chain.Unless otherwise defined, otherwise these alkane Base usually contains 1 to 10 carbon atoms and includes such as-C1-4Alkyl ,-C1-5Alkyl ,-C2-5Alkyl ,-C1-6Alkyl and-C1-10Alkane Base.Representative alkyl includes such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the second butyl, isobutyl group, the tert-butyl group, just Amyl group, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl etc..
When certain number of carbon atom is intended for use particular term used herein, the number of carbon atom is with subscript shape Before formula is illustrated in described term.Such as distinguishing, term "-C1-6Alkyl " mean the alkyl with 1 to 6 carbon atoms, and Term "-C3-7Cycloalkyl " mean the cycloalkyl with 3 to 7 carbon atoms, wherein carbon atom is in any acceptable configuration.
Term " alkylidene " means can be the divalent saturated hydrocarbon base of straight chain or branched chain.Unless otherwise defined, otherwise these Alkylidene usually contains 0 to 10 carbon atoms and includes such as-C0-1Alkylidene-,-C0-6Alkylidene-and-C1-3Alkylidene-.Generation Table alkylidene include such as methylene, ethane-1,2-diyl (" ethylidene "), propane-1,2-diyl, propane-1,3-diyl, Butane-1,4-diyl, pentane-1,5-diyl etc..Should be appreciated that when alkylidene term includes 0 carbon, as-C0-1Alkylidene-time, These terms it is intended to not exist carbon atom, i.e. there is not Asia in addition to connecting by the covalent bond of the separate group of alkylene ground term Alkyl.
Term " aryl " means the monovalent aromatic race hydrocarbon with single ring (i.e. phenyl) or one or more fused rings. Fused ring system include complete undersaturated fused ring system (such as naphthalene) and the undersaturated fused ring system of part (such as 1, 2,3,4-naphthane).Unless otherwise defined, otherwise these aryl usually contain 6 to 10 carboatomic ring atoms and include such as-C6-10 Aryl.Representative aryl includes such as phenyl and naphthalene-1-base, naphthalene-2-base etc..
Term " cycloalkyl " means unit price saturated carbon ring alkyl.Unless otherwise defined, otherwise these cycloalkyl usually contain 3 To 10 carbon atoms and include such as-C3-5Cycloalkyl ,-C3-6Cycloalkyl and-C3-7Cycloalkyl.Representative cycloalkyl includes such as Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
Term " halogen " means fluorine, chlorine, bromine and iodine.
Term " heterocycle " it is intended to have single ring or two fused rings unsaturated (aromatic series) heterocycle of unit price and Have that the unit price of single ring or multiple condensed ring is saturated and part unsaturated group.Heterocycle can be containing amounting to 3 to 15 annular atomses, its In 1 to 14 annular atomses be ring carbon atom, and 1 to 4 annular atomses are the ring hetero atom selected from nitrogen, oxygen or sulfur.But, generally, Heterocycle contains 3 to 10 annular atomses of total, and wherein 1 to 9 annular atomses are ring carbon atom, and 1 to 4 annular atomses are that ring is miscellaneous former Son.Junction point is at any available carbon or nitrogen ring atom.Exemplary heterocyclic includes such as-C1-7Heterocycle ,-C3-5Heterocycle ,-C2-6 Heterocycle ,-C3-12Heterocycle ,-C5-9Heterocycle ,-C1-9Heterocycle ,-C1-11Heterocycle and-C1-14Heterocycle.
Unit price unsaturated heterocycle is also commonly referred to as " heteroaryl ".Unless otherwise defined, otherwise heteroaryl usually contains total 5 To 10 annular atomses, wherein 1 to 9 annular atomses are ring carbon atom, and 1 to 4 annular atomses are ring hetero atom, and include such as- C1-9Heteroaryl and-C5-9Heteroaryl.Representative heteroaryl includes such as pyrroles's (such as 3-pyrrole radicals and 2H-pyrroles's-3-base), miaow Azoles (such as 2-imidazole radicals), furan (such as 2-furyl and 3-furyl), thiophene (such as 2-thienyl), triazole (such as 1, 2,3-triazolyl and 1,2,4-triazolyl), pyrazoles (such as 1H-pyrazole-3-yl), azoles (such as 2-oxazolyl), isoxazole (example Such as 3-isoxazolyl), thiazole (such as 2-thiazolyl and 4-thiazolyl) and isothiazole (such as 3-isothiazolyl), pyridine (such as 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals), Pyridinylimidazoles, Triazolopyridine, pyrazine, pyridazine (such as 3-pyridazinyl), phonetic Pyridine (such as 2-pyrimidine radicals), tetrazolium, triazine (such as cyanuro 1,3,5), indole (such as 1H-indole-2-base, 1H-indole-4- Base and 1H-indole-5-base), benzofuran (such as benzofuran-5-base), benzothiophene (such as benzo [b] thiophene-2-base and Benzo [b] thiophene-5-base), benzimidazole, benzothiazole, benzothiazole, benzotriazole, quinoline (such as 2-quinolyl), isoquinoline Quinoline, quinazoline, quinoxaline etc..
Unit price saturated heterocyclic usually contains 3 to 10 annular atomses of total, and wherein 2 to 9 annular atomses are ring carbon atom, and 1 It is ring hetero atom to 4 annular atomses, and includes such as-C3-5Heterocycle.Representative unit price saturated heterocyclic includes such as unit price kind Pyrrolidine, imidazolidine, pyrazolidine, piperidines, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrrolin etc..In certain situation Under, part can be described as forming the saturated-C optionally containing oxygen atom in ring together3-5Heterocycle.These groups include:
Monovalent moiety unsaturated heterocycle usually contains 3 to 10 annular atomses of total, and wherein 2 to 11 annular atomses are that ring carbon is former Son, and 1 to 3 annular atomses are ring hetero atom, and include such as-C3-5Heterocycle and-C2-12Heterocycle.Representative monovalent moiety insatiable hunger Such as pyrans .alpha.-5:6-benzopyran, benzodioxole (such as benzo [1,3] dioxole-5-is included with heterocycle Base), tetrahydro pyridazine, 2,5-dihydro-1H-pyrroles, glyoxalidine, dihydro triazole, dihydro azoles, dihydro isoxazole, thiazoline, Dihydro isothiazole, dihydrooxadiazole, thiodiazoline, tetrahydro pyridazine, hexahydropyrrolo quinoxaline and dihydro oxa-diazine And [e].In some cases, part can be described as forming part unsaturation-C together3-5Heterocycle.These groups include:
Term " is optionally substituted " and means that described group can be unsubstituted or it can be substituted one or for several times, such as 1 to 3 times or 1 to 5 times.For example, the phenyl of " optionally replacing through halogen atom " can be unsubstituted, or it can be former containing 1,2,3,4 or 5 halogen Son.
As used herein, phrase " there is formula " or " there is structure " be not intended to have restricted and with Essential Terms " bag Containing " identical mode uses.
Term " pharmaceutically acceptable " refers to not be the most unacceptable or at it The unacceptable material of its aspect.For example, term " pharmaceutically acceptable supporting agent " refer to may be incorporated in compositions and Unacceptable biological effect or mutual with other component of compositions in unacceptable mode is not caused to patient's administration The material of effect.These pharmaceutically acceptable materials have the most met for toxicology and have manufactured the standard needed for test and bag Include and differentiated as being suitable for nonactive one-tenth by food and drug administration (U.S.Food and Drug administration) The material divided.
Term " pharmaceutically acceptable salt " means from can be to patient, the alkali accepted such as mammal administration or acid The salt (such as there is for predetermined dose scheme the salt of acceptable mammalian safety) of preparation.It should be appreciated, however, that The salt that the present invention is contained is not required to as pharmaceutically acceptable salt, as being not intended to the intermediate compound to patient's administration Salt.Pharmaceutically acceptable salt may originate from pharmaceutically acceptable inorganic base or organic base, and come from and pharmaceutically may be used The mineral acid accepted or organic acid.Additionally, when compound of formula I contains basic moiety (such as amine, pyridine or imidazoles) and acidic moiety Time both (such as carboxylic acid or tetrazolium), amphion can be formed and it is included in as the term is employed herein in " salt ".Come from medicine On, the salt of acceptable inorganic base includes ammonium salt, calcium salt, mantoquita, iron salt, ferrous salt, lithium salts, magnesium salt, manganese salt, manganous salt, potassium Salt, sodium salt and zinc salt etc..The salt coming from pharmaceutically acceptable organic base includes the salt of following thing: primary amine, secondary amine and uncle Amine, including being substituted amine, cyclammonium, naturally-produced amine etc., such as arginine, glycine betaine (betaine), caffeine (caffeine), choline (choline), N, N'-benzhydryl ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino Ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine (glucamine), glycosamine (glucosamine), histidine, Kazakhstan amine (hydrabamine), 2-aminopropane., lysine, methylglucosamine, morpholine, piperazine, piperazine Pyridine, polyamino resin, procaine (procaine), purine, theobromine (theobromine), triethylamine, trimethylamine, tripropyl amine (TPA), Trometamol (tromethamine) etc..The salt coming from pharmaceutically acceptable mineral acid includes the salt of following acid: boric acid, Carbonic acid, halogen acids (hydrobromic acid, hydrochloric acid, Fluohydric acid. or hydroiodic acid), nitric acid, phosphoric acid, sulfamic acid and sulphuric acid.Come from pharmaceutically The salt of acceptable organic acid includes the salt of following acid: aliphatic hydroxyl acid (such as citric acid, gluconic acid, glycolic, breast Acid, lactobionic acid, malic acid and tartaric acid), aliphatic monocarboxylic acid (such as acetic acid, butanoic acid, formic acid, propanoic acid and trifluoroacetic acid), ammonia Base acid (such as aspartic acid and glutamic acid), aromatic carboxylic acid (such as benzoic acid, parachlorobenzoic-acid, diphenyl acetic acid, gentisic acid (gentisic acid), hippuric acid (hippuric acid) and triphenylacetic acid), aromatic hydroxyl acid (such as adjacent oxybenzene first Acid, p-hydroxybenzoic acid, 1-hydroxyl naphthalene-2-formic acid and 3-hydroxyl naphthalene-2-formic acid), ascorbic acid, dicarboxylic acids (such as fumaric acid, horse Come sour, oxalic acid and succinic acid), glucuronic acid, mandelic acid, mucic acid, nicotinic acid, orotic acid, pamoic acid, pantothenic acid, sulfonic acid (example Such as benzenesulfonic acid, camphorsulfonic acid, 1,2-ethane disulfonic acid (edisylic acid), ethane sulfonic acid, isethionic acid, Loprazolam, naphthalene Sulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-methyl benzenesulfonic acid), former times naphthoic acid (xinafoic acid) etc..
As used herein, term " prodrug " is it is intended to mean that the most such as turn by normal metabolic processes It is melted into nonactive (or activity is the least) prodrug of its activity form.Described term is also intended to include to remove final Some of the compound of formula I prepared before the protection group stage is through the derivant of protection.These compounds may not have medicine to NEP Activity of science, but orally available or parenteral administration and metabolism the most in vivo, thus form the basis that NEP is had pharmacological activity Invention compound.Therefore, all derivants through protection and the prodrug of compound of formula I is included within the scope of the invention.Tool The prodrug having the compound of formula I of free carboxy can be easy to be synthesized by the technology known in technique.These prodrug derivants Then pass through solvolysis or change into free carboxy compound in physiological conditions.Exemplary prodrug includes ester, such as C1-6Alkyl Ester and aryl-C1-6Arrcostab.In one embodiment, compound of formula I has free carboxy and prodrug is its ester derivant, i.e. Prodrug is such as-C (O) OCH2CH3Ester.
Term " therapeutically effective amount " means the amount that be enough to realize treatment when to patient's administration in need, is acquisition institute Want the medication amount needed for response to treatment.For example, the therapeutically effective amount for the treatment of hypertension for such as alleviating, contain, eliminate or Compound amount needed for the symptom of prophylaxis of hypertension or the cause of disease of hiding for the treatment of hypertension.In one embodiment, treatment is effectively Amount is the medication amount needed for reduce blood pressure required medication amount or maintenance normal arterial pressure.On the other hand, term " effective dose " meaning Refer to the amount that be enough to obtain the desired result that may be therapeutic outcome.For example, when research comprises the system of NEP enzyme, " effective dose " can be to suppress the amount needed for described enzyme.
" treat (treating) " as the term is employed herein or " treatment (treatment) " means to treat patient, as fed The disease of breast animal (being especially the mankind) or Medical Condition (such as hypertension), this includes one or more aspects following: (a) Prevention disease or Medical Condition occur, i.e. prevention disease or Medical Condition recurrence or prophylactic treatment is prone to suffer from disease or medical science The patient of condition of illness；B () improves disease or Medical Condition, i.e. eliminate the disease of patient or Medical Condition or make disease or the doctor of patient Condition of illness disappears；C () containment disease or Medical Condition, i.e. slow down or check the disease of patient or the development of Medical Condition；Or (d) Alleviate the disease of patient or the symptom of Medical Condition.For example, term " treatment hypertension " will include prophylaxis of hypertension occur, Improve hypertension, containment hypertension and the symptom (such as reducing blood pressure) of alleviating hypertension.Term " patient " it is intended to needs Treatment or disease prevention or currently accept treatment with reach disease prevention treatment specified disease or Medical Condition suckling move Thing (such as the mankind) and assess in analysis or use the test of the compounds of this invention individual, such as animal model.
Other terms all used herein are intended to have the one being appreciated by one of skill in the art that such as it As implication.
In an aspect, the present invention relates to compound of formula I:
Or its pharmaceutically acceptable salt.
As used herein, term " the compounds of this invention " includes all compounds contained by Formulas I, as with Formulas I a to Il body Existing congener；And the compound contained by Formula II.Additionally, the compounds of this invention also can contain some alkalescence or acidic-group (such as amino or carboxyl) and therefore these compounds can exist with free alkali, free acid form or with various salt forms.All These salt forms are included within the scope of the invention.Additionally, the compounds of this invention can exist with prodrug forms.Therefore, institute Genus field skilled artisans appreciated that unless otherwise instructed, the most referenced herein compound, such as mention " of the present inventionization Compound " or " compound of formula I " include compound of formula I and the pharmaceutically acceptable salt of described compound and prodrug.It addition, Term " or its pharmaceutically acceptable salt and/or prodrug " it is intended to all arrangements of salt and prodrug, such as the medicine of prodrug Acceptable salt on.Additionally, the solvate of compound of formula I is included within the scope of the invention.
Compound of formula I can contain one or more chiral centres and therefore these compounds can be with various stereoisomerisms Form preparation and use.Therefore, unless otherwise instructed, otherwise the invention still further relates to racemic mixture, pure stereoisomers (example Such as enantiomer and diastereomer), stereoisomer enriched Mixture etc..When being described herein as without any three-dimensional During the chemical constitution learned, it should be understood that this structure contains all possible stereoisomer.So that it takes up a position, for example, term " Formulas I Compound ", " Formula II compound " etc. it is intended to all possible stereoisomer of compound.Similarly, when opening up in this article When showing or name particular stereoisomer, it will be understood by one of ordinary skill in the art that unless otherwise instructed, otherwise a small amount of other stands Body isomer is likely to be present in the present composition, and its restrictive condition is that the overall utility of compositions is not because existing these other Isomer and eliminate.Numerous methods that individual stereoisomers can pass through known in technique obtain, including using applicable hands Property fixing mutually or the chiral chromatogram of supporter obtains, or by it chemically being changed into diastereomer, utilize such as The conventional means separation diastereomer of chromatograph or recrystallization, then regeneration original stereo isomer obtains.
It addition, unless specified otherwise herein, the most as applicable, the compounds of this invention all cis-anti-or E/Z isomer is (several What isomer), tautomeric form and topoisomerase form be included within the scope of the invention.For example, if X describes Become (R5For hydrogen):
So should be appreciated that compound can also exist such as following tautomeric form:
More precisely, compound of formula I is at R2Contain at least one chiral centre during for H, and work as R2For-OR20Shi Han There is at least two chiral centre.These chiral centres are indicated by symbol * and * * in following formula I a and Ib:
In a stereoisomer of Formulas I a compound, * * symbol the carbon atom differentiated has (R) configuration.The present invention This embodiment show in Formulas I a-1:
In this embodiment, compound has (R) configuration or rich in having (R) structure at this carbon atom at * * carbon atom The stereoisomeric forms in any ratio of type.In another stereoisomer of Formulas I a compound, * * symbol the carbon atom differentiated has (S) structure Type.This embodiment of the present invention shows in Formulas I a-2:
In this embodiment, compound has (S) configuration or rich in having (S) structure at this carbon atom at * * carbon atom The stereoisomeric forms in any ratio of type.
In one stereoisomer of Formulas I b compound, * and * * symbol two carbon atoms differentiated have (R) configuration. This embodiment of the present invention shows in Formulas I b-1:
In this embodiment, compound has (R, R) configuration at * and * * carbon atom or has rich at these carbon atoms There is the stereoisomeric forms in any ratio of (R, R) configuration.In another stereoisomer of Formulas I b compound, * and * * symbol two differentiated Individual carbon atom has (S) configuration.This embodiment of the present invention shows in Formulas I b-2:
In this embodiment, compound has (S, S) configuration at * and * * carbon atom or has rich at these carbon atoms There is the stereoisomeric forms in any ratio of (S, S) configuration.In another stereoisomer of Formulas I b compound, symbol * the carbon atom differentiated There is (S) configuration and the carbon atom by symbol * * discriminating has (R) configuration.This embodiment of the present invention shows in Formulas I b-3:
In this embodiment, compound has (S, R) configuration at * and * * carbon atom or has rich at these carbon atoms There is the stereoisomeric forms in any ratio of (S, R) configuration.In another stereoisomer of Formulas I b compound, symbol * the carbon atom differentiated There is (R) configuration and the carbon atom by symbol * * discriminating has (S) configuration.This embodiment of the present invention shows in Formulas I b-4:
In this embodiment, compound has (R, S) configuration at * and * * carbon atom or has rich at these carbon atoms There is the stereoisomeric forms in any ratio of (R, S) configuration.
The compounds of this invention and its synthesis in use compound may also include through isotope-labeled compound, i.e. its In one or more atoms with having the former of the atomic mass that is different from nature main seen atomic mass Son enrichment.The isotopic example that may be incorporated in compound of formula I such as includes, but is not limited to2H、3H、13C、14C、15N、18O、17O、35S、36Cl and18F.Especially relevant is to can be used for the Formulas I chemical combination rich in tritium or carbon-14 in such as tissue distribution research Thing；The especially compound of formula I rich in deuterium at the site of metabolism producing the compound such as with relatively greater metabolic stability；With Can be used in the research of such as positron emission tomography (Positron Emission Topography, PET) rich in just Electron emission isotope (as11C、18F、15O and13N) compound of formula I.
Herein for naming the nomenclature of the compounds of this invention to be illustrated in example herein.This nomenclature makes With commercially available AutoNom software (the MDL company of California Sheng Laiandeluo (MDL, San Leandro, California)) obtain.
Representative embodiment
Substituents and value intend to provide various aspects and the representative example of embodiment of the present invention.These are representative Value is intended additionally define and illustrate these aspects and embodiment and be not intended to exclude other embodiments or limit the scope of the present invention. In this, unless specifically indicated, otherwise particular value or substituent group preferably state be not intended to by any way from the present invention arrange Except other value or substituent group.
In one embodiment, the present invention relates to compound of formula I:
R1It is selected from-OR10With-NR60R70。R10Part is selected from H ,-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3 Alkylidene-C1-9Heteroaryl ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene- NR14R15、-C1-6Alkylidene-C (O) R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
Wherein R13It is selected from-C1-6Alkyl ,-O-C1-6Alkyl ,-C3-7Cycloalkyl ,-O-C3-7Cycloalkyl, phenyl ,-O-benzene Base ,-NR14R15With-CH (NH2)CH2COOCH3；R14And R15Independently selected from H ,-C1-6Alkyl and benzyl, or R14And R15Together Formation-(CH2)3-6-、-C(O)-(CH2)3-or-(CH2)2O(CH2)2-；R16For-C1-6Alkyl or-C0-6Alkylidene-C6-10Aryl； And R17It is selected from-O-C1-6Alkyl ,-O-benzyl and-NR14R15。R60Part is selected from H ,-OH ,-OC (O) R61、-CH2COOH、- O-benzyl, pyridine radicals and-OC (S) NR62R63；Wherein R61It is selected from H, C1-6Alkyl ,-C6-10Aryl ,-OCH2-C6-10Aryl ,- CH2O-C6-10Aryl and-NR62R63；And R62And R63Independently be H or-C1-4Alkyl.R70Part is selected from H ,-C1-6Alkyl and-C (O)R71；Wherein R71It is selected from H ,-C1-6Alkyl ,-C3-7Cycloalkyl ,-C6-10Aryl and-C1-9Heteroaryl.
In one embodiment, R1For-OR10, and R10For H or-C1-6Alkyl (such as-CH2CH3With-(CH2)3CH3)。
In one embodiment, R1It is selected from-OR10With-NR60R70, wherein R10For H, R60For H or-OH, and R70For H.
In another embodiment, R1For-OR10, wherein R10It is selected from-C1-6Alkyl (such as-CH2CH3、-(CH2)2CH3、- CH(CH3)2、-CH2CH(CH3)2、-(CH2)3CH3、-(CH2)4CH3With-(CH2)2CH(CH3)2)、-C1-3Alkylidene-C6-10Aryl (such as benzyl) ,-C1-3Alkylidene-C1-9Heteroaryl ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3(such as-(CH2)2OCH3With- [(CH2)2O]2CH3)、-C1-6Alkylidene-OC (O) R13(such as-CH2-OC(O)CH3、-CH2-OC(O)CH2CH3With-CH2-OC(O) OCH2CH3)、-C1-6Alkylidene-NR14R15(such as-(CH2)2-N(CH3)2、
-C1-6Alkylidene-C (O) R17(such as-CH2C(O)OCH3、-CH2C (O) O-benzyl ,-CH2C(O)-N(CH3)2With
-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl (such as-(CH2)2SO2CH3)、
In another embodiment, R1For-NR60R70, wherein R60It is selected from-OC (O) R61、-CH2COOH ,-O-benzyl, pyrrole Piperidinyl and-OC (S) NR62R63；And R70For H.In another embodiment, R1For-NR60R70, wherein R60For H or-OH, and R70For- C1-6Alkyl or-C (O) R71.In another embodiment, R1For-NR60R70, wherein R60It is selected from-OC (O) R61、-CH2COOH、-O- Benzyl, pyridine radicals and-OC (S) NR62R63；And R70For-C1-6Alkyl or-C (O) R71.In one aspect of the invention, these Compound can be particularly useful as the intermedium in prodrug or synthesis program as herein described.For example, in one embodiment, R1For-OR10And R10For-C1-6Alkylidene-OC (O) R13, such as-O-CH (CH3) OC (O)-O-ring hexyl:
Come for former times (cilexetil) ester so that compound is west；Or R1For-OR10And R10For-C0-6Alkylidene morpholine, Such as-O-(CH2)2-morpholine:
So that compound is 2-(N-morpholinyl) ethyl ester or not coffee (mofetil) ester；Or R1For-OR10And R10For
Such as-O-CH2-5-methyl-[1,3] dioxole-2-ketone:
So that compound is wheat many Mils (medoxomil) ester.
R2It is selected from H and-OR20。R20Part is H or together with R10Formation-CR together21R22-or together with R60Formation-C together (O)-；Wherein R21And R22Independently selected from H ,-C1-6Alkyl and-O-C3-7Cycloalkyl, or R21And R22Formation=O together.At one In embodiment, R2It is selected from H and-OR20, wherein R20For H.
Work as R2For-OR20And R20Together with R10Formation-CR together21R22In-time, this embodiment can be described as:
And work as R21And R22Together during formation=O, this embodiment can be described as:
Work as R2For-OR20And R20Together with R60Formation-NHC (O) together-time, this embodiment can be described as:
In one aspect of the invention, during these compounds can be particularly useful as prodrug or synthesis program as herein described Intermedium.
R3It is selected from H, Cl, F ,-CH3With-CF3.In one embodiment, R3It is selected from H, Cl and-CF3。
" X " part is-C1-10Heteroaryl or part unsaturation-C3-12Heterocycle, its restrictive condition is that X is not for pyrazoles.X is pyrrole The compound of azoles is described in the commonly assigned title belonging to Jin Delun (Gendron) et al. and is " enkephalinase inhibitor (Neprilysin Inhibitors) " on May in 2011 31 submit to U.S. Provisional Application case the 61/491,750th and with The U. S. application case the day submitted to _ _ _ _ _ _ _ _ number (attorney docket P-285-US1) in.It should be noted that in certain embodiments, R4、R5And/or R6Can not exist.When it is present, R4And/or R6On any available carbon atom.When it is present, R5Any available On nitrogen-atoms.In certain embodiments, " part is-C to X1-10Heteroaryl, the example includes:
Pyrroles:
As
Furan:
As
Thiophene:
As
Imidazoles is such as:
Its particular instance includes:
Triazole, including 1,2,3-triazoles, such as:
And 1,2,4-triazoles, such as:
Azoles:
Its particular instance includes:
Isoxazole:
Its particular instance includes:
Thiazole:
Its particular instance includes:
Isothiazole:
Diazole, including [1,2,4] diazole, such as:
And [1,2,3] diazole, such as:
[1,3,4] diazole:
Thiadiazoles, including [1,2,4] thiadiazoles, such as:
And [1,2,3] thiadiazoles, such as:
[1,3,4] thiadiazoles:
Tetrazolium, such as:
Pyridine:
Its particular instance includes:
Pyrazine:
As
Pyrimidine:
Its particular instance includes:
Pyridazine:
As
Benzimidazole is such as:
Its particular instance includes:
Benzotriazole:
Its particular instance includes:
Benzothiazole is such as:
Its particular instance includes:
Benzothiazole is such as:
Its particular instance includes:
Pyridinylimidazoles is such as:
Its particular instance includes:
Triazolopyridine is such as:
Its particular instance includes:
Imidazopyridine is such as:
Its particular instance includes:
Pyrrolopyrimidine is such as:
Its particular instance includes:
5-oxa--3,3a-diaza cyclopentano [a] naphthalene:
As
In one embodiment, X is part unsaturation-C2-12Heterocycle, the example includes:
Glyoxalidine:
As
Dihydro triazole is such as:
Dihydro azoles:
As
Dihydro isoxazole:
As
Thiazoline:
As
Dihydro isothiazole:
As
Dihydrooxadiazole:
As
Thiodiazoline:
As
Tetrahydro pyridazine:
As
Hexahydropyrrolo quinoxaline are such as
Its particular instance includes:
Dihydro oxa-diaza benzo [e]:
As
In a particular embodiment, X be selected from pyrroles, furan, thiophene, imidazoles, triazole, azoles, isoxazole, thiazole, Isothiazole, diazole, thiadiazoles, tetrazolium, pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, benzothiazole, benzo Thiazole, Pyridinylimidazoles, Triazolopyridine, imidazopyridine, pyrrolopyrimidine, 5-oxa--3,3a-diaza cyclopentano [a] Naphthalene, glyoxalidine, dihydro triazole, dihydro azoles, dihydro isoxazole, thiazoline, dihydro isothiazole, dihydrooxadiazole, dihydro Thiadiazoles, tetrahydro pyridazine, hexahydropyrrolo quinoxaline and dihydro oxa-diaza benzo [e].
In a particular embodiment, X be selected from furan, thiophene, imidazoles, triazole, azoles, isoxazole, pyridine, pyrazine, Pyrimidine, pyridazine, benzimidazole, benzotriazole, Pyridinylimidazoles, Triazolopyridine, imidazopyridine, pyrrolopyrimidine, 5-oxygen Miscellaneous-3,3a-diaza cyclopentano [a] naphthalene, dihydro triazole, dihydro isoxazole, tetrahydro pyridazine, hexahydropyrrolo quinoxaline and dihydro Oxa-diaza benzo [e].
R4Part can not exist.When it is present, R4It is attached partially to carbon atom and is selected from H；Halogen；-C0-5Alkylidene- OH；-NH2；-C1-6Alkyl；-CF3；-C3-7Cycloalkyl；-C0-2Alkylidene-O-C1-6Alkyl；-C(O)R40；-C0-1Alkylidene-C (O) OR41；-C(O)NR42R43；-NHC(O)R44；=O；-NO2；Furan；Pyrazine；Naphthalene；Pyridine；Optionally through methyl substituted pyrazoles；Appoint Choosing is through methyl substituted thiophene；With optionally warp selected from halogen ,-OH ,-CF3、-OCH3、-NHC(O)CH3A group with phenyl Substituted phenyl；And when X is pyridazine, pyrazine and pyridine, R4Can be also through-C (O) OR41Substituted phenyl.R40Part be H or- C1-6Alkyl.R41Part is selected from H ,-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylidene-C1-9Heteroaryl ,-C3-7 Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、-C1-6Alkylidene-C (O) R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
R13It is selected from-C1-6Alkyl ,-O-C1-6Alkyl ,-C3-7Cycloalkyl ,-O-C3-7Cycloalkyl, phenyl ,-O-phenyl ,- NR14R15With-CH (NH2)CH2COOCH3；R14And R15Independently selected from H ,-C1-6Alkyl and benzyl, or R14And R15Shape together One-tenth-(CH2)3-6-、-C(O)-(CH2)3-or-(CH2)2O(CH2)2-；R16For-C1-6Alkyl or-C0-6Alkylidene-C6-10Aryl；And R17It is selected from-O-C1-6Alkyl ,-O-benzyl and-NR14R15。R42And R43Part is independently selected from H ,-C1-6Alkyl ,- CH2COOH、-(CH2)2OH、-(CH2)2OCH3、-(CH2)2SO2NH2、-(CH2)2N(CH3)2、-C3-7Cycloalkyl and-(CH2)2-miaow Azoles；Or R42And R43Form saturated or part unsaturation-C together3-5Heterocycle, it is optionally through-OH ,-COOR41Or-CONH2Replace and Optionally containing oxygen atom in described ring.R44Part is selected from-C1-6Alkyl；-C0-1Alkylidene-O-C1-6Alkyl；Optionally through halogen Base or-OCH3Substituted phenyl；With-C1-9Heteroaryl.
In one embodiment, R4It is selected from H；Halogen (such as chlorine, fluorine and bromine)；-C0-5Alkylidene-OH (such as-OH)；- C1-6Alkyl (such as-CH3、-CH2CH3、-(CH2)2CH3With-(CH2)3CH3)；-C0-1Alkylidene-C (O) OR41(such as- COOR41)；=O；Optionally through a halogen (such as chlorine) substituted phenyl；With the warp-C (O) when X is pyridazine, pyrazine and pyridine OR41Substituted phenyl；And R41It is selected from H and-C1-6Alkyl (such as-CH2CH3)。
In a particular embodiment, R4For-C0-1Alkylidene-C (O) OR41, wherein R41For H.At another specific embodiment In, R4For-C0-1Alkylidene-C (O) OR41, wherein R41It is selected from-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylene Base-C1-9Heteroaryl ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、- C1-6Alkylidene-C (O) R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
In one aspect of the invention, these compounds below can be particularly useful as prodrug or synthesis as herein described Intermedium in program.
R5Part can not exist.When it is present, R5It is attached partially to nitrogen-atoms and is selected from H；-C1-6Alkyl；-C0-3Alkylene Base-OH；-[(CH2)2O]1-3CH3；-C1-3Alkylidene-C (O) OR50；-CH2-C(O)NR51R52；Optionally through the substituted-C of halogen0-2 Alkylene-pyridine；Optionally through methyl substituted-CH2-isoxazole；Optionally through-O-C1-6Substituted-the CH of alkyl2-pyrimidine；-C2Sub- Alkyl-phenyl；
R50Part is selected from H ,-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylidene-C1-9Heteroaryl ,-C3-7 Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、-C1-6Alkylidene-C (O) R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
Wherein R13It is selected from-C1-6Alkyl ,-O-C1-6Alkyl ,-C3-7Cycloalkyl ,-O-C3-7Cycloalkyl, phenyl ,-O-benzene Base ,-NR14R15With-CH (NH2)CH2COOCH3；R14And R15Independently selected from H ,-C1-6Alkyl and benzyl, or R14And R15Together Formation-(CH2)3-6-、-C(O)-(CH2)3-or-(CH2)2O(CH2)2-；R16For-C1-6Alkyl or-C0-6Alkylidene-C6-10Aryl； And R17It is selected from-O-C1-6Alkyl ,-O-benzyl and-NR14R15。R51And R52Part is independently selected from H ,-C1-6Alkyl ,- CH2COOH、-(CH2)2OH、-(CH2)2OCH3、-(CH2)2SO2NH2、-(CH2)2N(CH3)2、-C3-7Cycloalkyl and-(CH2)2-miaow Azoles；Or R52And R53Form saturated or part unsaturation-C together3-5Heterocycle, it is optionally through-OH ,-COOR41Or-CONH2Replace and Optionally containing oxygen atom in described ring.R53、R54、R55、R56And R57Part is independently selected from H, halogen ,-C1-6Alkyl ,-O- C1-6Alkyl and-S-C1-6Alkyl, the most each-C1-6Alkyl optionally replaces through 1 to 5 fluorine atoms.
In one embodiment, R5Do not exist or selected from H；-C0-3Alkylidene-OH (such as-OH and-(CH2)3OH)；- C1-3Alkylidene-C (O) OR50(such as-CH2C(O)OR50)；-CH2-C(O)NR51R52；Optionally replace through a halogen (such as bromine) -C0-2Alkylene-pyridine, such as:
Wherein R50For H；R51And R52For H；R53It is selected from H, halogen (such as fluorine) and-O-C1-6Alkyl (such as-OCH3)；R54 It is selected from H and halogen (such as fluorine)；R55It is selected from H, halogen (such as chlorine) and-O-C1-6Alkyl (such as-OCH3)；R56For H；And R57For H.
In a particular embodiment, R5For-C1-3Alkylidene-C (O) OR50, wherein R50For H.At another specific embodiment In, R5For-C1-3Alkylidene-C (O) OR50, wherein R50It is selected from-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylene Base-C1-9Heteroaryl ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、- C1-6Alkylidene-C (O) R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
In one aspect of the invention, these compounds below can be particularly useful as prodrug or synthesis as herein described Intermedium in program.
R6Can not exist.When it is present, R6It is attached partially to carbon atom and is selected from H, halogen ,-OH ,-C1-6Alkyl and-O- C1-6Alkyl.In one embodiment, R6Do not exist or selected from H, halogen (such as chlorine and fluorine) ,-OH and-C1-6Alkyl (such as- CH3)。
The particular instance of compound of formula I includes the compound of Formulas I c to Il as described below.In one embodiment, R2For- OR20, R20For H, and R3For Cl, it can be as described by Formulas I c:
In an exemplary embodiment of Formulas I c compound, R1For-OR10；R10For H or-C1-6Alkyl；X is selected from furan Mutter, triazole, azoles, isoxazole, pyridine, pyrazine, pyrimidine, benzotriazole, Pyridinylimidazoles, Triazolopyridine, imidazopyridine, 5-oxa--3,3a-diaza cyclopentano [a] naphthalene, tetrahydro pyridazine and dihydro oxa-diaza benzo [e]；R4It is selected from H；Halogen Base；-C0-5Alkylidene-OH；-C1-6Alkyl；-C0-1Alkylidene-C (O) OR41；=O；Optionally through a substituted phenyl of halogen, and When X is pyrazine and pyridine through-C (O) OR41Substituted phenyl；R41For H or-C1-6Alkyl；R5Do not exist or selected from H ,-C0-3 Alkylidene-OH,
R53For H or halogen；R54For H or halogen；R55It is selected from H, halogen and-O-C1-6Alkyl；R56For H；R57For H；And R6 Do not exist or selected from H, halogen ,-OH and-C1-6Alkyl.
In another embodiment, R2For-OR20, R20For H, and R3For-CF3, it can describe such as Formulas I d:
In the exemplary embodiment of Formulas I d compound, R1For-OR10；R10For H or-C1-6Alkyl；X is Triazolopyridine； R4For H；R5For H；And R6For H.
In another embodiment, R2For-OR20；R20For H；And R3For H, it can be described such as Formulas I e:
In the exemplary embodiment of Formulas I e compound, R1For-OR10；R10For H or-C1-6Alkyl；X is selected from thiophene, miaow Azoles, pyridine, pyrazine, pyridazine, benzimidazole, benzotriazole, Triazolopyridine, pyrrolopyrimidine and hexahydropyrrolo quinoxaline； R4It is selected from H；Halogen；-C1-6Alkyl；-C0-1Alkylidene-C (O) OR41；=O；With when X is pyridazine, pyrazine or pyridine, through-C (O)OR41Substituted phenyl；R41For H or-C1-6Alkyl；R5Do not exist or selected from H；-C0-3Alkylidene-OH；-C1-3Alkylidene-C (O)OR50；-CH2-C(O)NR51R52；Optionally through the substituted-C of halogen0-2Alkylene-pyridine；
R50For H；R51And R52For H；R53For H or-O-C1-6Alkyl；R54For H；R55For H or-O-C1-6Alkyl；R56For H；R57 For H；And R6Do not exist or selected from H and halogen.
In one embodiment, R2For-OR20, R20For H and R3For-CH3, it can describe such as Formulas I f:
In another embodiment, R2For-OR20, R20For H and R3For F, it can be described such as Formulas I g:
In one embodiment, R2For H and R3For Cl, it can be described such as Formulas I h:
In an exemplary embodiment of Formulas I h compound, R1For-OR10；R10For H or-C1-6Alkyl；X is selected from three Azoles, pyridine, pyrimidine, pyridazine, benzotriazole and Triazolopyridine；R4It is selected from H, halogen ,-C0-5Alkylidene-OH ,-C1-6Alkyl With warp-C (O) OR when X is pyridazine or pyridine41Substituted phenyl；R41For H；R5Do not exist or for H；And R6Do not exist or for H.
In another embodiment, R2For H and R3For-CF3, it can describe such as Formulas I i:
In another embodiment, R2For H and R3For H, it can be described such as Formulas I j:
In one embodiment, R2For H and R3For-CH3, it can describe such as Formulas I k:
In another embodiment, R2For H and R3For F, it can be described such as Formulas I l:
In another embodiment, R1For-OR10；R10For H or-C1-6Alkyl；X is selected from thiophene, imidazoles, triazole, azoles, different Azoles, pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzotriazole, Pyridinylimidazoles, Triazolopyridine, imidazopyridine, Pyrrolopyrimidine, 5-oxa--3,3a-diaza cyclopentano [a] naphthalene, dihydro triazole, dihydro isoxazole, tetrahydro pyridazine, hexahydro pyrrole Cough up and quinoxaline and dihydro oxa-diaza benzo [e]；R4It is selected from H；Halogen；-C0-5Alkylidene-OH；-C1-6Alkyl；- C0-1Alkylidene-C (O) OR41；=O；Optionally through a substituted phenyl of halogen；With the warp-C when X is pyridazine, pyrazine or pyridine (O)OR41Substituted phenyl；R41It is selected from H and-C1-6Alkyl；R5Do not exist or selected from H；-C0-3Alkylidene-OH；-C1-3Alkylene Base-C (O) OR50；-CH2-C(O)NR51R52；Optionally through the substituted-C of halogen0-2Alkylene-pyridine；
R50For H；R51And R52For H；R53It is selected from H, halogen and-O-C1-6Alkyl；R54For H or halogen；R55It is selected from H, halogen Base and-O-C1-6Alkyl；R56For H；R57For H；And R6Do not exist or selected from H, halogen ,-OH and-C1-6Alkyl.An enforcement In example, these compounds have Formulas I c to Il.In other compound, these compounds have selected from H and-OR20R2, wherein R20For H；And R3It is selected from H, Cl and-CF3。
Additionally, relevant specific compound of formula I includes in following instance institute exponent and it is pharmaceutically acceptable Salt.
General synthesis program
The compounds of this invention can use the program illustrated in following conventional method, example from the initial substance system being easily obtained Standby, or use those skilled in the art's other method known, reagent and initial substance to be prepared.Although follow procedure Only certain embodiments of the present invention can be described, it will be appreciated that other embodiments of the invention can use same or like method or pass through Those skilled in the art's other method known, reagent and initial substance is used to be prepared similarly.Should also be clear that and remove Non-other statement, is otherwise specifying typical case or preferably processing conditions (such as reaction temperature, time, the mol ratio of reactant, molten Agent, pressure etc.) in the case of, it is possible to use other processing conditions.In some cases, at room temperature carry out reacting and not obtaining Actual temperature measurement result.In should be appreciated that room temperature may be used to mean the scope the most relevant to the ambient temperature in laboratory environment Temperature and generally will be in the range of about 18 DEG C to about 30 DEG C.In other cases, at room temperature carry out reacting and actual survey Measure and record temperature.Although optimum reaction condition is by generally regarding various response parameters used, such as specific reactants, solvent sum Measure and change, but those skilled in the art can easily be used routine optimization program and determines applicable reaction condition.
It addition, as being apparent from for those skilled in the art is aobvious, GPF (General Protection False base can be to prevent some functional group's warp Go through undesirable reaction institute required or required.Select be applicable to the protection group of particular functional group and be applicable to protect these Functional group and remove the condition of its protection group and reagent in the art it is well known that.If desired, can use except as herein described The protection group beyond protection group illustrated in program.For example, numerous protection groups and its introducing and removal are described in T.W. lattice Woods (T.W.Greene) and G.M. watt hereby (G.M.Wuts), protection group (the Protecting Groups in organic synthesis Organic Synthesis), fourth edition, the Willie publishing house (Wiley, New York) in New York, 2006 and ginseng cited therein Examine in document.More precisely, following abbreviation and reagent are for flow process presented below:
P1Representing " carboxyl-protecting group ", one is used for meaning to be suitable to prevent from occurring at carboxyl undesirable reaction herein The term of protection group.Representative carboxyl-protecting group include, but is not limited to methyl, ethyl, the tert-butyl group, benzyl (Bn), to methoxy Base benzyl (PMB), 9-fluorenyl methyl (Fm), TMS (TMS), t-butyldimethylsilyi (TBDMS), hexichol Ylmethyl (benzhydryl, DPM) etc..Standard deprotection base technology and reagent are used for removing P1Group, and visually base used by it Roll into a ball and change.For example, sodium hydroxide or Lithium hydrate are generally at P1For using during methyl, the acid such as TFA or HCl generally exists P1For using when ethyl or the tert-butyl group, and H2/ Pd/C can be at P1For using during benzyl.
P2Representing " amino protecting group ", one is used for meaning to be suitable to prevent from occurring at amino undesirable reaction herein The term of protection group.Representative amino protecting group includes, but is not limited to tert-butoxycarbonyl (BOC), trityl (Tr), benzene Methoxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl groups (Fmoc), formoxyl, TMS (TMS), fert-butyidimethylsilyl Silylation (TBDMS) etc..Standard deprotection base technology is used for removing P2Group.For example, BOC group can use acid examination Agent, is removed such as the DCM containing TFA or containing the Isosorbide-5-Nitrae-dioxane of HCl, and Cbz group can by using catalytic hydrogenation conditions, as H2(1 atmospheric pressure) and 10%Pd/C (" H in alcohol solvent2/ Pd/C ") removed.
P3Representing " hydroxyl protecting group ", one is used for meaning to be suitable to prevent from occurring at hydroxyl undesirable reaction herein The term of protection group.Representative hydroxyl protecting group includes, but is not limited to C1-6Alkyl；Silylation, including three C1-6Alkyl silane Base, such as TMS (TMS), triethyl silyl (TES) and t-butyldimethylsilyi (TBDMS)；Ester (acyl group), Including C1-6Alkanoyl, such as formoxyl, acetyl group and pivaloyl group, and aromatic acyl, such as benzoyl；Aryl methyl, such as benzene Methyl (Bn), to mehtoxybenzyl (PMB), 9-fluorenyl methyl (Fm) and diphenyl methyl (benzhydryl, DPM)；Deng.Standard Deprotection base technology and reagent are used for removing P3Group, and visually group used by it and change.For example, H2/ Pd/C is usual At P3For using during benzyl, and NaOH is generally at P3For using during acyl group.
Alkali (passing through way of illustration and not by way of limitation) be applicable to these flow processs include potassium carbonate, calcium carbonate, sodium carbonate, Triethylamine, pyridine, 1,8-diazabicylo-[5.4.0] 11-7-alkene (DBU), N, N-diisopropylethylamine (DIPEA), 4-first Base morpholine, sodium hydroxide, potassium hydroxide, potassium tert-butoxide and metal hydride.
Inert diluent or solvent (passing through way of illustration and not by way of limitation) be applicable to these flow processs include tetrahydrochysene furan Mutter (THF), acetonitrile (MeCN), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), toluene, dichloromethane (DCM), chloroform (CHCl3), carbon tetrachloride (CCl4), 1,4-dioxane, methanol, ethanol, water Deng.
Carboxylic acid/amine the coupling reagent being suitable for includes hexafluorophosphoric acid benzotriazole-1-base epoxide three (dimethylamino) (BOP), hexafluorophosphoric acid benzotriazole-1-base epoxide three (N-pyrrolidinyl) (PyBOP), hexafluorophosphoric acid N, N, N', N'-tetramethyl Base-O-(7-azepine benzo triazol-1-yl) urea (HATU), 1,3-dicyclohexyl carbodiimide (DCC), N-(3-dimethylamino Propyl group)-N'-ethylcarbodiimine (EDCI), carbonyl dimidazoles (CDI), I-hydroxybenzotriazole (HOBt) etc..Coupling reaction It is to carry out in inert diluent in the presence of such as the alkali of DIPEA, and carries out under the conditions of conventional amide key-like becomes.
Responded at a temperature of all generally in the range of about-78 DEG C to 100 DEG C, the most at room temperature carried out.Reaction Can monitor until completing by using thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and/or LCMS.Reaction can count Complete in minute, maybe can take hours, usual 1 to 2 hours and up to 48 hours.In the completed, gained mixture or reaction Product can process to obtain desired product further.For example, gained mixture or product can be performed one or one Individual above follow procedure: concentrate or distribute and (be such as allocated between EtOAc and water or be allocated in EtOAc and 1M containing 5%THF Between phosphoric acid)；Extraction is (such as with EtOAc, CHCl3, DCM, chloroform extraction)；Washing is (such as with NaCl saturated aqueous solution, saturated NaHCO3、Na2CO3(5%), CHCl3Or 1M NaOH washing)；It is dried (such as through MgSO4、Na2SO4It is dried or vacuum drying)； Filter；Crystallization (such as crystallizes from EtOAc and hexane)；Concentrate (being such as concentrated in vacuo)；And/or purification is (such as silica gel chromatography, fast Speed chromatograph, preparation HPLC, reversed-phase HPLC or crystallization).
Compound of formula I and its salt can be prepared as shown in flow process I:
Flow process I
Compound 1 and compound 2 coupling.At R1For such as-OCH3Or-OCH2CH3Group situation in, Coupling step it After can be that deprotection base step is to provide compound of formula I, wherein R1Group for such as-OH.Therefore, the compounds of this invention is prepared A kind of method relate to making compound 1 and compound 2 coupling, and optional deprotection base step, to form compound of formula I Or its pharmaceutically acceptable salt.
Compound of formula I and its salt (wherein R4For being optionally substituted phenyl) also can prepare as shown in flow process II:
Flow process II
Additionally, such as flow process I, this is the standard coupling reaction obtaining compound 3 between compound 1 and compound 2a, Wherein L is leaving group, such as halogen (such as bromine and chlorine).Compound 3 then with the 4,4,5,5-tetramethyl-2-benzene being optionally substituted Base-[1,3,2] dioxy boron pentane reacts in the coupling reaction of palladium chtalyst.In order to prepare R4For being unsubstituted the Formulas I of phenyl Compound, then R is hydrogen.Or, R is selected from halogen ,-OH ,-CF3、-OCH3、-NHC(O)CH3And phenyl.When X is pyridazine, pyrazine Or during pyridine, R can be also-C (O) OR41.The exemplary dioxy boron pentane being substituted includes 2-tert-butoxycarbonyl phenyl boric acid frequency Any alcohol ester.
The coupling reaction of palladium chtalyst is generally entered in the presence of applicable alkali (such as potassium carbonate or sodium carbonate) in inert diluent OK, and afterwards can be that deprotection base step is to provide compound of formula I, wherein R1Group for such as-OH.Therefore, this is prepared The other method of bright compound relates to making compound 1 and compound 2a coupling to form compound 3, makes compound 3 and optional warp Substituted 4,4,5,5-tetramethyl-2-phenyl-[1,3,2] dioxy boron pentane coupling, and optional deprotection base step with Form compound of formula I or its pharmaceutically acceptable salt.
Compound of formula I and its salt (wherein R4For being optionally substituted phenyl) also can prepare as shown in flow process III:
Flow process III
Such as flow process I, first step be compound 2b and 4,4,5, the 5-tetramethyl-2-phenyl being optionally substituted-[1, 3,2] forming the coupling reaction of palladium chtalyst of compound 4 between dioxy boron pentane, wherein L is leaving group, as halogen (such as bromine and Chlorine), and P1For selected from methyl, ethyl, the tert-butyl group, benzyl, to mehtoxybenzyl, 9-fluorenyl methyl, TMS, T-butyldimethylsilyi and the carboxyl-protecting group of benzhydryl.Compound 4 then with compound 1 coupling, be optional afterwards Deprotection base step to provide compound of formula I, wherein R1Group for such as-OH.Therefore, the another of the compounds of this invention is prepared One method relates to 4,4,5,5-tetramethyl-2-phenyl-[1,3,2] dioxy boron pentane coupling making compound 2b with being optionally substituted To form compound 4, make compound 4 and compound 1 coupling, and optional deprotection base step is to form compound of formula I Or its pharmaceutically acceptable salt.
Compound 1,2,2a and 2b is commercially available maybe can use in program known in the art and present example Prepared by the program illustrated.
Some intermedium as herein described is considered as novel, and correspondingly, described compound is as the present invention's Other side provides, including such as Formula II compound or its salt:
Wherein P is selected from-O-P1、-NHP2With-NH (O-P3)；P1For selected from methyl, ethyl, the tert-butyl group, benzyl, to first Epoxide benzyl, 9-fluorenyl methyl, TMS, t-butyldimethylsilyi and the carboxyl-protecting group of benzhydryl； P2For selected from tert-butoxycarbonyl, trityl, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl groups, formoxyl, trimethyl silane Base and the amino protecting group of t-butyldimethylsilyi；And P3For selected from C1-6The hydroxyl of alkyl, silylation, ester and aryl methyl Base protection group；And R2To R6It is as defined for Formulas I.Therefore, the other method preparing the compounds of this invention relates to removing Formula II The protection group of compound.
About other of the preparation representative compound of the present invention or the special reaction condition of its intermedium and other program Details are been described by following example.
Effectiveness
The compounds of this invention has enkephalinase (NEP) inhibitory activity, and the most described compound can suppress enzymatic activity. In another embodiment, compound on vascular angiotensin-converting enzyme does not represent remarkable inhibiting activity.Compound suppression NEP activity The one of ability is measured as inhibition constant (pKi)。pKiValue is dissociation constant (Ki) the negative logarithm with 10 as the end, it is generally to rub You report unit.Especially relevant the compounds of this invention is the pK to NEPiCompound more than or equal to 6.0, especially pKiIt is more than Or the compound equal to 7.0, and the most especially pKiCompound more than or equal to 8.0.In one embodiment, relevantization The pK of compoundiIn the range of 6.0 to 6.9；In another embodiment, the pK of related compoundiIn the range of 7.0 to 7.9； In another embodiment, the pK of related compoundiIn the range of 8.0 to 8.9；And in another embodiment, related compound PKiIn the range of more than or equal to 9.0.These values can pass through the technology known in technique and as herein described Analysis measures.
Another of the ability of compound suppression NEP activity is measured as apparent inhibition constant (IC50), it is for making NEP enzyme the end of to The molar concentration of the compound that the conversion of thing is suppressed by half maximum.pIC50Value is IC50The negative logarithm with 10 as the end.Especially Relevant the compounds of this invention includes representing the pIC to NEP50Compound greater than or equal to about 5.0.Related compound also includes PIC to NEP50>=about 6.0 or pIC to NEP50The compound of >=about 7.0.In another embodiment, related compound pair The pIC of NEP50In the range of about 7.0 to 11.0；And in another embodiment, in the range of about 8.0 to 11.0, as about In the range of 8.0 to 10.0.
It should be noted that in some cases, the compounds of this invention is likely to be of faint NEP inhibitory activity.In these situations Under, those skilled in the art will be appreciated that these compounds still have the effectiveness as research tool.
Measure the character of the compounds of this invention, as the exemplary analysis of NEP inhibitory activity is described in example and (by saying Bright and unrestriced mode) include measuring the analysis (being described in analysis 1) that NEP suppresses.The secondary analysis being suitable for includes measuring ACE suppression (being also described in analysis 1) and amino peptidase P (APP) suppression (are described in Suhl Pi Qiao (Sulpizio) et al. (2005) in pharmacology and experimental therapeutic magazine (JPET) 315:1306-1313) analysis.Assessment is to ACE in anesthetized rat Be described in analysis 2 with the pharmacodynamic analysis of the internal suppression usefulness of NEP (referring also to west rub (Seymour) et al. (1985) high Blood pressure (Hypertension) 7 (supplementary issue I): I-35-I-42 and Wei Gele (Wigle) et al. (1992) Canada physiology and medicine Magazine (Can.J.Physiol.Pharmacol.) 70:1525-1528 of science), wherein ACE suppression is measured as angiotensin The suppression percentage ratio of I booster reaction and NEP suppression are measured as purine guanosine 3', the increase of 5'-monophosphate (cGMP) output.
Exist and can be used for determining many In vivo analysis of other effectiveness of the compounds of this invention.The high blood of sentient spontaneity Pressure rat (SHR) model is a kind of feritin (renin) dependent hypertension model, and is described in analysis 3.Referring also to Yin Tegan Et al. (Intengan) (1999) circulation (Circulation) 100 (22): 2267-2275 and hundred morals sub-(Badyal) et al. (2003) India pharmacology magazine (Indian Journal of Pharmacology) 35:349-362.Sentient acetic acid takes off Oxygen corticosterone-salt (DOCA-salt) rat model is a kind of volume dependent hypertension model being applicable to measure NEP activity, and It is described in analysis 4.Referring also to Trapani (Trapani) et al. (1989) cardiovascular pharmacology magazine (J.Cardiovasc.Pharmacol.)14:419-424；Yin Tegan et al. (1999) hypertension 34 (4): 907-913 and hundred morals Asia et al. (2003) (ibid).DOCA-salt model is particularly well-suited to ability and the measurement that assessment test compound reduces blood pressure The ability that test compound prevention or delay blood pressure rise.Dahl brine sensitivity (DSS) hypertensive rat model is a kind of to meals The hypertension model that feeding habits salt (NaCl) is sensitive, and be described in analysis 5.Referring also to drawing general (Rapp) (1982) hypertension 4: 753-763.It is described in the rat open country hundred such as added in rattan (Kato) et al. (2008) cardiovascular pharmacology magazine 51 (1): 18-23 Close the reliable prediction that alkali (monocrotaline) pulmonary hypertension model is a kind of clinical efficacy treating pulmonary hypertension Model.Heart failure animal model includes DSS rat model and aortocaval fistula model (the sound short pulse of heart failure Road (AV shunt)), latter of which is described in such as nephropathy association of promise woods (Norling) et al. (1996) U.S. magazine (J.Amer.Soc.Nephrol.) in 7:1038-1044.Other animal model is (such as hot plate, whipping (tail-flick) He Fuer Malin (formalin) tests) and Spinal nerve ligation (SNL) model of Neuropathic Pain can be used for measuring of the present inventionization The analgesic properties of compound.See for example Malmberg (Malmberg) et al. (1999) Neuroscience Laboratory guide (Current Protocols in Neuroscience)8.9.1-8.9.15。
Expection the compounds of this invention can suppress NEP in above listed any analysis or the analysis with similar characteristics Enzyme.Therefore, above-mentioned analysis is applicable to determine the treatment effectiveness of the compounds of this invention, and such as it is as antihypertensive agents Or the effectiveness of antidiarrheal.Other character of the compounds of this invention and effectiveness can use its known to those skilled in the art Its in vitro and in vivo analysis is proved.Compound of formula I can be active medicine and prodrug.Therefore, when discussing chemical combination of the present invention During thing active, it should be understood that these prodrugs any may not represent expection activity in analysis, it is anticipated that it is once through metabolism, i.e. Represent and wanted activity.
Expection the compounds of this invention is applicable to the Medical Condition that NEP suppression is reacted by treatment and/or prevention.Therefore, in advance Phase is suffered from and can be passed through by the patient of suppression NEP enzyme or the disease treated by increasing the content of its peptide substrates or disease The compounds of this invention of administration therapeutically effective amount is treated.For example, it is contemplated that these compounds can be strengthened by suppression NEP Endogenous peptide that NEP metabolism produces is (such as natriuretic peptide, bell toad element (bombesin), Kallidin I, calcitonin (calcitonin), interior Pi Su (endothelin), enkephalin, neurotensin (neurotensin), Substance P and vasoactive intestinal peptide (vasoactive intestinal peptide)) biological effect.It is therefore contemplated that these compounds such as to kidney system, in Pivot nervous system, reproductive system and gastronintestinal system have other physiological action.
In one embodiment of the invention, the patient suffering from disease or the disease treated by suppression NEP enzyme is It is the compounds of this invention of its activity form, i.e. compound of formula I by administration and is treated, wherein R1It is selected from-OR10 With-NR60R70, wherein R10For H, R60For H or-OH, and R70For H；And R2、R3、X、R4、R5And R6It is as defined for Formulas I.
In another embodiment, patient be by administration metabolism in vitro with form the compound of compound of formula I and in addition Treatment, wherein R1It is-OR10Or-NR60R70；R10It is H, R60It is H or-OH, R70It is H；And R2、R3、X、R4、R5And R6It is as right Defined in Formulas I.
In another embodiment, patient is at R by administration1The compounds of this invention in its prodrug forms at group, i.e. Compound of formula I and treated, wherein:
R1For-OR10；And R10It is selected from-C1-6Alkyl ,-C1-3Alkylidene-C6-10Aryl ,-C1-3Alkylidene-C1-9Heteroaryl Base ,-C3-7Cycloalkyl ,-[(CH2)2O]1-3CH3、-C1-6Alkylidene-OC (O) R13、-C1-6Alkylidene-NR14R15、-C1-6Alkylidene- C(O)R17、-C0-6Alkylidene morpholine ,-C1-6Alkylidene-SO2-C1-6Alkyl,
R1For-NR60R70；R60It is selected from-OC (O) R61、-CH2COOH ,-O-benzyl, pyridine radicals and-OC (S) NR62R63； And R70For H；Or
R1For-NR60R70；R60It is selected from-OC (O) R61、-CH2COOH ,-O-benzyl, pyridine radicals and-OC (S) NR62R63； And R70For-C1-6Alkyl or-C (O) R71；Or
R1For-NR60R70；R60For H or-OH；And R70For-C1-6Alkyl or-C (O) R71；Or
R1For-OR10；R2For-OR20；And R20Together with R10Formation-CR together21R22-；Or
R1For-NR60R70；R2For-OR20；And R20Together with R60Formation-C (O) together-；And R2、R3、X、R4、R5、R6、R13、 R14、R15、R16、R17、R21、R22、R61、R62、R63And R71It is as defined for Formulas I.
Cardiovascular disease
Expection the compounds of this invention can be applicable to control such as natriuretic peptide and the effect of Kallidin I by strengthening vasoactive peptide Treat and/or prevention is such as the Medical Condition of cardiovascular disease.See for example Roc this (Roques) et al. (1993) pharmacological review (Pharmacol.Rev.) 45:87-146 and Dempsey (Dempsey) et al. (2009) American Journal of Pathology (Amer.J.of Pathology)174(3):782-796.Especially relevant cardiovascular disease includes hypertension and heart failure.Hypertension (is passed through Way of illustration and not by way of limitation) including: essential hypertension, it is also referred to as this state property hypertension or essential hypertension；Secondary Property hypertension；Hypertension with nephropathy；With or without the severe hypertension of nephropathy；Pulmonary hypertension is high including pulmonary artery Blood pressure；And intractable hypertension.Heart failure (passing through way of illustration and not by way of limitation) including: congestive heart failure；Acute Heart failure；Chronic heart failure, such as with left ventricular ejection fraction reduce (also referred to as contractility heart failure) or with Left ventricular ejection fraction keeps (also referred to as diastolic heart failure)；With acute and chronic decompensation heart failure, with or Without nephropathy.Therefore, one embodiment of the present of invention relates to one and treats hypertension, specifically essential hypertension or lung The method of Arterial Hypertention, it comprises the compounds of this invention to patient's administration therapeutically effective amount.
For treatment essential hypertension, therapeutically effective amount usually be enough to reduce the amount of the blood pressure of patient.This includes gently Degree is to moderate hypertension and severe hypertension.When being used for treating hypertension, compound can be thrown with other therapeutic combination With, other therapeutic agent described such as aldosterone (aldosterone) antagonist, aldosterone synthase inhibitor, angiotensin turn Change enzyme inhibitor and dual function angiotensin converting enzyme/enkephalinase inhibitor, angiotensin converting enzyme 2 (ACE2) Activator and stimulant, Angiotensin II vaccine, anti-diabetic medicament, lipotropism matter medicament, antithrombotic agent, AT1Receptor is short of money Anti-agent and dual function AT1Receptor antagonist/enkephalinase inhibitor, β1-adrenergic aceptor antagonist, dual function Property B-adrenergic receptor antagonist/α1-receptor antagonist, calcium channel blocker, diuretic, endothelin-receptor antagonists, Endothelin-converting enzyme inhibitor, enkephalinase inhibitor, natriuretic peptide and its analog, natriuretic peptide remove receptor antagonist, an oxygen Change nitrogen donor, non-steroid anti-inflammatory agent, phosphodiesterase inhibitor (PDE-V inhibitor specifically), prostaglandin (prostaglandin) receptor stimulating agent, renin inhibitor, sGC (guanylate cyclase) thorn Swash agent and activator and a combination thereof.In one particular embodiment of the present invention, the compounds of this invention and AT1Receptor antagonist, Calcium channel blocker, diuretic or a combination thereof combine and are used for treating essential hypertension.Another particular implementation in the present invention In example, the compounds of this invention and AT1Receptor antagonist combines and for treating the hypertension with nephropathy.When being used for treating stubbornness During property hypertension, described compound can with such as other therapeutic combination administration of aldosterone synthase inhibitors.
For treatment pulmonary hypertension, therapeutically effective amount usually be enough to reduce the amount of pulmonary vascular resistance.Its of therapy Its purpose is to improve the motor capacity of patient.For example, in a clinical configuration, therapeutically effective amount can be improvement patient The amount of the ability of the comfortable walking period of 6 minutes (containing the distance of about 20 meters to 40 meters).When being used for treating pulmonary hypertension Time, compound can be with other therapeutic combination administration, other therapeutic agent described such as alpha-adrenergic aceptor antagonist, β1-kidney Upper parathyrine energy receptor antagonist, β2-3 adrenergic receptor agonists, angiotensin-convertion enzyme inhibitor, anticoagulant, calcium are logical Road blocker, diuretic, endothelin-receptor antagonists, PDE-V inhibitor, prostaglandin analogue, selective serotonin are taken the photograph again Take inhibitor and a combination thereof.In one particular embodiment of the present invention, the compounds of this invention and PDE-V inhibitor or selectivity Serotonin reuptake inhibitors combines and is used for treating pulmonary hypertension.
Another embodiment of the present invention relates to one and treats heart failure, and congestive heart failure (includes receiving specifically Contracting and diastolic congestive heart failure) method, it comprises the chemical combination of the present invention to patient's administration therapeutically effective amount Thing.Generally, therapeutically effective amount is the amount that be enough to reduce blood pressure and/or improve renal function.In a clinical configuration, treatment is effectively Amount can be to be enough to improve cardiac hemodynamics, as such as reduced wedge pressure (wedge pressure), right atrial pressure, filling pressure Amount with vascular resistance.In one embodiment, compound is with intravenous dosage form administration.When being used for treating heart failure, Compound can be with other therapeutic combination administration, and is produced from other therapeutic agent described such as adenosine receptor antagonists, terminal glycosylation end eventually Thing decomposition agent, aldosterone antagonists, AT1Receptor antagonist, β1-adrenergic aceptor antagonist, dual function β-adrenal gland Element can receptor antagonist/alpha 1-receptor antagonist, rotten enzyme (chymase) inhibitor, digoxin (digoxin), diuretic, endothelium Element invertase (ECE) inhibitor, endothelin-receptor antagonists, natriuretic peptide and its analog, natriuretic peptide remove receptor antagonist, one Nitric oxide donor, prostaglandin analogue, PDE-V inhibitor, soluble guanylate cyclase activators and stimulant and blood vessel Vassopressin (vasopressin) receptor antagonist.In one particular embodiment of the present invention, the compounds of this invention and aldosterone Antagonist, β1-adrenergic aceptor antagonist, AT1Receptor antagonist or diuretic combinations, and be used for treating congestive cardiac Exhaustion.
Diarrhoea
Expection the compounds of this invention can suppress degraded and therefore these chemical combination of endogenous enkephalins as nep inhibitor Thing could be applicable to treatment diarrhoea, including infectious and secreted/watery diarrhea.See for example Bao Mo (Baumer) et al. (1992) intestinal (Gut) 33:753-758；New (Farthing) (2006) digestive disease (Digestive Diseases) 24 of method: 47-58；Many with Ma Ersai-Ke La(1987) Europe pharmacology's magazine (Eur.J.Pharmacol.) 144(2):125-132.When being used for treating diarrhoea, the compounds of this invention can combine with one or more other diarrheas.
Nephropathy
Expection the compounds of this invention can be by strengthening vasoactive peptide, as the effect of natriuretic peptide and Kallidin I strengthens kidney merit (old (Chen) et al. (1999) circulation 100:2443-2448 can be seen；Li Pujin (Lipkin) et al. (1997) International Nephrology (Kidney Int.)52:792-801；With Di Suole (Dussaule) et al. (1993) Clinical Science (Clin.Sci.) 84:31- 39), and be applicable to treatment and/or prevention nephropathy.Especially relevant nephropathy include diabetic nephropathy, chronic renal disease, Albuminuria, and especially acute injury of kidney or acute renal failure (see Sha Er Koffsky (Sharkovska) et al. (2011) Clinical laboratory (Clin.Lab.) 57:507-515 and nanowatt prick (Newaz) et al. (2010) renal failure (Renal Failure) 32:384-390).When being used for treating nephropathy, compound can with other therapeutic agent, as angiotensin-convertion enzyme inhibitor, AT1Receptor antagonist and diuretic combinations administration.
Preventative therapy
Due to natriuretic peptide, there is anti-hypertrophy and fibrosis effect (sees baud (Potter) et al. (2009) experimental drug Handbook (Handbook of Experimental Pharmacology) 191:341-366 of science), therefore it is also contemplated that the present invention Compound can be applicable to preventative therapy by strengthening the effect of natriuretic peptide, such as prevent cardiac insufficiency after myocardial infarction Progress, after angioplasty after prevention of arterial restenosis, vascular surgery prevention blood vessel wall is thickening, prevention of arterial medicated porridge sample is hard Change and prevention of diabetic vascular pathological changes.
Glaucoma
Expection the compounds of this invention can be applicable to by strengthening the effect of natriuretic peptide treat glaucoma.See for example Di Si Te Er Philip Hurst (Diestelhorst) et al. (1989) international ophthalmology (International Ophthalmology) 12: 99-101.When being used for treating glaucoma, the compounds of this invention can combine with one or more other glaucoma medicaments.
Ease the pain
Expection the compounds of this invention can suppress degraded and therefore these chemical combination of endogenous enkephalins as nep inhibitor Thing is also applicable to make analgesic.See for example Roc this et al. (1980) natural (Nature) 288:286-288 and base of a fruit Navarre Et al. (Thanawala) medicine target (Current Drug Targets) 9:887-894 in (2008) present age.When being used for treating pain Time, the compounds of this invention can combine with one or more other analgesics, described medicine such as aminopeptidase N or two peptidyls Peptidase III inhibitor, non-steroid anti-inflammatory agent, monoamine re-uptake inhibitor, muscle relaxant, nmda receptor antagonist, opium Sample nonopioid receptors agonist, 5-HT1DSerotonin receptor agonist and tricyclic antidepressants.
Other effectiveness
Due to the NEP inhibition activity of the compounds of this invention, therefore it is also contemplated that it is useful as antitussive and is applicable to treatment To following relevant portal hypertension: liver cirrhosis (sees Sang Suo (Sansoe) et al. (2005) hepatopathy magazine (J.Hepatol.) 43:791-798), cancer (see Wei Saili (Vesely) (2005) Research of Medical magazine (J.Investigative Med.) 53:360-365), depressed (see Noble (Noble) et al. (2007) therapeutic targets special Family suggestion (Exp.Opin.Ther.Targets) 11:145-159), menoxenia, premature labor (preterm labor), before eclamposia (such as masculinity and femininity infertility, polycystic ovary is comprehensive for phase (pre-eclampsia), endometriosis, reproduction disorders Disease, graft failure (implantation failure)) and masculinity and femininity sexual dysfunction, including male erectile dysfunction Disease is aroused with Female sexual.More particularly, it is contemplated that the compounds of this invention is applicable to treat female sexual disorder and (sees general relying Moral (Pryde) et al. (2006) journal of medicinal chemistry (J.Med.Chem.) 49:4409-4424), it is often defined as female patient Property cannot or hardly be expressed and please oneself.This contains multiple different female sexual disorder, (by illustrative not limiting Mode) include that hyposexuality disease (hypoactive sexual desire disorder), sexual arousal disease, orgasm are sick Disease and property antalgesic.When being used for treating these diseases, especially during female sexual disorder, the compounds of this invention can with a kind of or More than one following second pharmaceutical agent combinations: PDE-V inhibitor, dopamine (dopamine) agonist, estrogen receptor agonist And/or antagonist, androgen and estrogen.NEP inhibition activity owing to the compounds of this invention, it is also contemplated that it has anti-inflammatory Matter, and expect that it has such effectiveness, when being especially applied in combination with Statins (statins).
Recently research shows that NEP is in the neural merit of regulation in insulin deficit diabetes and meals induction property obesity Can aspect work.Ku Pei (Coppey) et al. (2011) neuro pharmacology (Neuropharmacology) 60:259-266.Cause This, owing to the NEP inhibition activity of the compounds of this invention, it is also contemplated that it is applicable to provide prevention by diabetes or meals induction property The nervous lesion that obesity causes.
Every dose of administration amount of the compounds of this invention or total administration amount every day can predefine or it can lead to based on few patients Crossing consideration many factors to be determined, described factor includes character and the seriousness of patient condition；The condition of illness treated；Patient's Age, body weight and general health；Patient's toleration to active agents；Dosing way；Pharmacology considers, such as institute's administration Compound and activity, effect, pharmacokinetics and the toxicology profiles of any second medicament；Deng.Treatment disease or medical science The patient of condition of illness (such as hypertension) can with predetermined close or the dosage determined by treating physician, and be pre-by continuing one section Prevent, improve, contain or palliate a disease or period necessary to the symptom of Medical Condition.The patient standing this treatment generally will be by often Rule monitoring is with the effectiveness determining therapy.For example, when treating hypertension, blood pressure measurement can be used for determining treatment Effectiveness.Other diseases as herein described index similar with condition of illness is it is well known that and easily obtained by treating physician.Doctor is carried out even Continuous monitoring will ensure that the compounds of this invention at any given time administration optimised quantity, and aids in determining whether continuing for the treatment of Time.When also administration the second medicament, this measure is the most valuable, because the holding of selection, dosage and the therapy of described second medicament The continuous time is likely to need to adjust.In this way, therapeutic scheme can be adjusted over the course for the treatment of and be administered time-histories so that administration exhibition As long as showing the minimum flow active agents of wanted effectiveness and it addition, successful treatment disease or Medical Condition are required, just can throw continuously Medicine.
Research tool
Because the compounds of this invention has NEP enzyme inhibition activity, so these compounds are also useful as detecting or studying tool There are the biosystem of NEP enzyme or the research tool of sample, in order to the disease that such as research NEP enzyme or its peptide substrates work.Tool Any applicable biosystem or the sample that have NEP enzyme can be used in these researchs that can external or internal carry out.Be suitable to these The representative biosystem of research or sample include, but is not limited to cell, cell extract, plasma membrane, tissue samples, separated Organ, mammal (such as mice, rat, Cavia porcellus, rabbit, Canis familiaris L., pig, the mankind etc.) etc., wherein mammal is especially relevant.At this In a bright specific embodiment, the NEP enzymatic activity in mammal be the compounds of this invention by administration NEP amount of suppression and Suppressed.The compounds of this invention is used as research tool also by using these compounds to carry out bioanalysis.
When as research tool, generally make the present invention comprising the biosystem of NEP enzyme or sample with NEP enzyme level amount Compound contacts.After biosystem or sample are exposed to compound, use conventional program and equipment, as by combination point In analysis, measurement receptor combines or measures in functional selection ligand-mediated change and measures the effect of suppression NEP enzyme.Expose Contain and make cell or tissue contact with compound；Such as by intraperitoneal (i.p.), oral (p.o), intravenous (i.v.), subcutaneous Or suck administration etc. to mammal administration compound (s.c.).This determination step can relate to measure reaction (quantitative analysis) or can Relate to being observed (qualitative analysis).Reaction is measured and relates to such as using conventional program and equipment, such as enzyme activity assay Measure compound on organism system or the effect of sample and in functional selection, measure zymolyte or the change of product mediation. Analysis result can be used for level of activity and the amount being defined as realizing compound necessary to desired result, i.e. NEP enzyme level amount. Generally, determination step will relate to the effect measuring suppression NEP enzyme.
It addition, the compounds of this invention can be used as assessing the research tool of other compound, and therefore apply also for screening point To be found for example that the new compound with NEP inhibitory activity in analysis.In this way, in the compounds of this invention use being performed an analysis Reference material, to allow the result comparing the result obtained with test compound and obtaining with the compounds of this invention, thus differentiates tool There is the approximately equivalent or test compound (if present) of greater activity.For example, to one test compound or one group of survey The pK of examination compoundiData and the pK of the compounds of this inventioniData compare, thus differentiate the test with desired properties Compound, such as pKiValue approximates or is higher than the test compound (if present) of the compounds of this invention.The bag in this respect of the present invention Include generation and compare data (use and suitably analyze) and analyzing test data as embodiment out of the ordinary to differentiate dependence test Compound.Therefore, can be by the method assessment test compound comprised the steps of in bioanalysis: (a) is with testing compound Carry out bioanalysis to provide the first assay value；B () carries out described bioanalysis to provide the second analysis with the compounds of this invention Value；Wherein step (a) is before step (b), afterwards or carries out with step (b) simultaneously；(c) will be from the institute of step (a) State the first assay value to compare with described second assay value from step (b).Exemplary bio analysis includes NEP enzyme level Analyze.
Medical composition and composite
The compounds of this invention is generally with medical composition or formulation administration patient.These medical compositions can pass through Any acceptable dosing way administration patient, include, but is not limited to be administered orally, per rectum, transvaginal, per nasal, suction, locally (including percutaneous), through eye and parenteral admistration pattern.It addition, the compounds of this invention can such as be administered orally with multidose (example every day Such as every day twice, three times or four times), single daily dosage or single every weekly dose administration.Should be appreciated that and be suitable to specific dispensing pattern Any form (i.e. free alkali, free acid, pharmaceutically acceptable salt, solvate etc.) of the compounds of this invention all can use In medical composition discussed herein.
Therefore, in one embodiment, the present invention relates to a kind of comprise pharmaceutically acceptable supporting agent and of the present inventionization The medical composition of compound.If desired, compositions can contain other therapeutic agent and/or blender.When discussing compositions, " this Invention compound " it is alternatively referred to as in this article " active agents ", thus by itself and other component of composite, as supporting agent is distinguished. It is therefore to be understood that term " active agents " includes compound of formula I and the pharmaceutically acceptable salt of described compound, solvent Compound and prodrug.
The medical composition of the present invention usually contains the compounds of this invention of therapeutically effective amount.But, the skill of art Art personnel will be appreciated that medical composition can be containing more than therapeutically effective amount (as in large quantities of compositionss) or effective less than treatment Amount (being i.e. designed for repeatedly offeing medicine to realize the discrete units dosage of therapeutically effective amount).Generally, compositions will contain about 0.01 weight % is to the active agents of 95 weight %, and including about 0.01 weight % to 30 weight %, such as from about 0.01 weight % is to 10 Weight %, wherein actual amount is depending on composite self, dosing way, administration frequency etc..In one embodiment, be suitable to be administered orally The compositions of dosage form such as can contain about 5 weight % to 70 weight % or the active agents of about 10 weight % to 60 weight %.
Any conventional carrier or excipient can be used in the medical composition of the present invention.Select specific supporting agent or figuration The combination of agent or supporting agent or excipient will treat the dispensing pattern of particular patient or Medical Condition or the class of morbid state depending on being used for Depending on type.In this, preparation is suitable to the compositions of specific dispensing pattern completely at the technical ability model of technical staff of field of medicaments In enclosing.It addition, the supporting agent or the excipient that use in these compositionss are commercially available.By the way of further illustrating, conventional allotment Technology be described in following in: Lei Mingdun: pharmaceutical science and put into practice (Remington:The Science and Practice of Pharmacy), the 20th edition, the Donald Lippincott Williams of Baltimore, the Maryland State and White publishing house (Lippincott Williams&White,Baltimore,Maryland)(2000)；With H.C. Ansai you (H.C.Ansel) et al., pharmaceutical dosage form With drug delivery system (Pharmaceutical Dosage Forms and Drug Delivery Systems), the 7th edition, The Donald Lippincott Williams of Baltimore, the Maryland State and White publishing house (1999).
The representative example of the material that may act as pharmaceutically acceptable supporting agent includes, but is not limited to following each thing: Sugar, such as lactose, dextrose plus saccharose；Starch, such as corn starch and potato starch；Cellulose, as microcrystalline Cellulose spreads out with it Biology, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Powdered tragacanth；Fructus Hordei Germinatus；Gelatin；Talcum；Figuration Agent, such as cocoa butter and suppository wax；Oil, such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil；Two Alcohol, such as propylene glycol；Polyhydric alcohol, such as glycerol, Sorbitol, mannitol and Polyethylene Glycol；Ester, such as ethyl oleate and lauric acid second Ester；Agar；Buffer agent, such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Apyrogeneity matter water；Isotonic saline solution；Ringer's mixture (Ringer's solution)；Ethanol；Phosphate buffered solution；Compressed propellant gas, such as chlorofluorocarbons and HFC Thing；With other non-toxic compatible material used in medical composition.
Generally pass through abundant and fine mixing or blend active agents and pharmaceutically acceptable supporting agent and one or Composition optional more than kind prepares medical composition.The mixture of the homogeneous blending of gained then can use conventional program and equipment It is configured to or loads in tablet, capsule, pill, tank, cartridge case, allotter etc..
In one embodiment, medical composition is suitable to oral administration medicine supplying.The compositions being suitable to oral administration medicine supplying can be in following shape Formula: capsule, tablet, pill, buccal tablet, cachet, dragee, powder, granule；Solution in aqueous or non-aqueous liquid or Suspension；Oil-in-water type or water-in-oil liquid emulsion；Elixir or syrup；Deng；Each active agents containing scheduled volume.
When intending with solid dosage forms (capsule, tablet, pill etc.) oral administration medicine supplying, compositions generally will comprise active agents The supporting agent pharmaceutically acceptable with one or more, such as sodium citrate or dicalcium phosphate.Solid dosage forms also can comprise: fills out Fill agent or extender, such as starch, microcrystalline Cellulose, lactose, sucrose, glucose, mannitol and/or silicic acid；Binding agent, such as carboxylic Methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or arabic gum (acacia)；Wetting agent, as sweet Oil；Disintegrating agent, such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and/or sodium carbonate；Dissolving is prolonged Agent late, such as paraffin；Absorption enhancer, such as quaternary ammonium compound；Wetting agent, such as monostearate hexadecane alcohol ester and/or monostearate Glyceride；Absorbent, such as Kaolin (kaolin) and/or bentonite (bentonite clay)；Lubricant, such as Talcum, tristearin Acid calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and/or its mixture；Coloring agent；And buffer agent.
Releasing agent, wetting agent, coating materials, sweeting agent, flavoring agent and aromatic, preservative and antioxidant also are present in In medical composition.Exemplary coating materials for tablet, capsule, pill etc. includes the coating materials for enteric coating, such as neighbour Cellulose acetate phthalate, polyvinylacetate phthalate, Hydroxypropyl Methylcellulose Phathalate, methyl-prop Olefin(e) acid-methacrylate copolymer, cellulose acetate trimellitate, carboxymethylethylcellulose, succinic acid acetic acid hydroxypropyl Methylcellulose etc..The example of pharmaceutically acceptable antioxidant includes: water soluble antioxidant, such as ascorbic acid, partly Cystine hydrochloride, sodium bisulfate, sodium metasulfite, sodium sulfite etc.；Oil-soluble inhibitor, such as vitamin-c palmitate Ester, butylated hydroxyanisol, Yoshinox BHT, lecithin (lecithin), propylgallate, alpha-tocopherol (alpha-tocopherol) etc.；And metal-chelator, such as citric acid, ethylenediaminetetraacetic acid, Sorbitol, tartaric acid, phosphoric acid Deng.
Compositions it be also possible to use hydroxypropyl methyl cellulose or other polymeric matrix, the liposome of such as different proportion And/or microsphere allotment, thus the slowly release of active agents is provided or controls release.Additionally, the medical composition of the present invention Opacifiers can be contained, and can be formulated so that it optionally only or preferentially in the release of gastrointestinal specific part is lived with delayed mode Property medicament.The example of spendable embedding composition includes polymeric material and wax.Active agents is the most optionally with a kind of or one More than kind, above-mentioned excipient is together in micro-encapsulated form.
Be suitable to the liquid dosage form of oral administration medicine supplying and include the most pharmaceutically acceptable emulsion, microemulsion, solution, suspension Liquid, syrup and elixir.Liquid dosage form generally comprises active agents and inert diluent, such as water or other solvent, solubilizing agent and breast Agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, oil (such as Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, oxolane alcohol, poly- The fatty acid ester of ethylene glycol and sorbitan and its mixture.Suspension can contain suspending agent, tristearin as different in ethoxylation Alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline Cellulose, inclined aluminium hydroxide, bentonite (bentonite), Agar and Tragacanth and its mixture.
When intending to be administered orally administration, the medical composition of the present invention can be packed with unit dosage forms.Term " unit dosage forms " is Refer to the physics Individual cells being suitable to that patient is administered, when the most each unit individually or combines with one or more other unit Containing being computed producing the active agents of the scheduled volume of effect to be treated.For example, these unit dosage forms can be capsule, Tablet, pill etc..
In another embodiment, the present composition is suitable to inhalation dosing, and generally will be in aerosol or powder form.Logical Often use and know delivery apparatus, such as aerosol apparatus, dry powder or these compositionss of metered-dose inhaler administration.Sprayer device produces height Speed air-flow, it makes compositions atomisation carry in the respiratory tract of patient.A kind of exemplary spray device composite comprises work Property medicament dissolution is to form solution in supporting agent, or active agents through micronized and merges with supporting agent and formed to have and can breathe chi The suspension of very little micronized particles.Diskus administration is the active agents of free flowing powder form, and it is in intake period Between be scattered in the air-flow of patient.A kind of exemplary Dry powder formulations comprises active agents and excipient (such as lactose, starch, sweet Dew sugar alcohol, dextrose, polylactic acid, polylactide-co-glycolide and a combination thereof) dry blend.Metered-dose inhaler uses Compressed propellant gas releases the quantity active agents through measuring.A kind of exemplary determine dose formulations and comprise active agents in liquid Change the solution in propellant (such as chlorofluorocarbons or hydrofluoroalkane) or suspension.The optional component of these composites includes altogether Solvent, such as ethanol or pentane；And surfactant, such as sorbitan trioleate, oleic acid, lecithin, glycerol and Laurel Base sodium sulfate.These compositionss generally by by chilled or pressurization hydrofluoroalkane add containing active agents, ethanol (if Exist) and the fitted vessel of surfactant (if present) in prepare.For supending, make active agents micronized and Then merge with propellant.Or, suspension formulations can be by making the surfactant on the micronized particles of active agents Coating is spray-dried to be prepared.Composite then loads in the aerosol container of the part forming inhaler.
The compounds of this invention also can parenteral (such as by subcutaneous, intravenous, intramuscular or peritoneal injection) administration.Right In this type of administration, active agents is to provide with sterile solution, suspension or emulsion form.Prepare the exemplary molten of these composites Agent includes water, saline, low-molecular-weight alcohol (such as propylene glycol), Polyethylene Glycol, oil, gelatin, fatty acid ester (such as ethyl oleate) etc..Intestinal The outer composite of stomach also can contain one or more antioxidants, solubilizing agent, stabilizer, preservative, wetting agent, emulsifying agent and Dispersant.It is right that surfactant, other stabilizer or pH value regulator (acid, alkali or buffer agent) and antioxidant are particularly well-suited to Composite provides stability, such as, make the hydrolysis of ester and the amido link that may be present in compound be preferably minimized or avoid.Can lead to Cross use sterile injectable medium, antibacterial, filter, radiate or heat and make these composites aseptic.At a particular implementation In example, parenteral composite comprises cyclodextrin aqueous solution as pharmaceutically acceptable supporting agent.The cyclodextrin being suitable for includes containing There is the ring molecule of 6 or more than 6 the α-D-glucopyanosyl unit connected in Isosorbide-5-Nitrae position through binding, at amylase, β-ring In dextrin or cycloheptaamylose same.Exemplified cyclodextrins includes cyclodextrin derivative, such as hydroxypropyl and sulfonic acid butyl Ether ring dextrin, such as HP-β-CD and sulfonic acid butyl ether beta-schardinger dextrin-.The exemplary buffer of these composites includes base In the buffer of carboxylic acid, such as citrate, lactate and maleate buffer solution.
The compounds of this invention it be also possible to use known transdermal delivery system and excipient percutaneous administration.For example, compound Can blend with penetration enhancers (such as propylene glycol, polyethylene glycol monolaurate, azacycloalkyl-2-ketone etc.), and be incorporated to paster or In similar delivery system.If desired, these transdermal compositions can use other excipient, including gellant, emulsifying agent and Buffer agent.
Second medicament
The compounds of this invention can be individually used for treating disease or can be with one or more other therapeutic combinations to obtain Obtain effect to be treated.Therefore, in one embodiment, the medical composition of the present invention contains and the compounds of this invention administration altogether Other medicines.For example, compositions can additionally comprise one or more medicines (also referred to as " the second medicament ").These Therapeutic agent in the art it is well known that, and include adenosine receptor antagonists, alpha-adrenergic aceptor antagonist, β1On-kidney Adrenergic receptor antagonist, β2-3 adrenergic receptor agonists, dual function B-adrenergic receptor antagonist/α1- Receptor antagonist, Advanced glycation endproducts decomposition agent, aldosterone antagonists, aldosterone synthase inhibitor, aminopeptidase N Inhibitor, androgen, angiotensin-convertion enzyme inhibitor and dual function angiotensin converting enzyme/enkephalinase suppression Agent, angiotensin converting enzyme 2 activator and stimulant, Angiotensin II vaccine, anticoagulant, anti-diabetic medicament, antidiarrheal Medicament, glaucoma medicament, lipotropism matter medicament, Pain relief agents, antithrombotic agent, AT1Receptor antagonist and dual function AT1 Receptor antagonist/enkephalinase inhibitor and multi-functional angiotensin receptor blocker, bradykinin receptor antagonists, calcium channel Blocker, chymase inhibitor, digoxin, diuretic, dopamine agonist, endothelin-converting enzyme inhibitor, endothelin receptor are short of money Anti-agent, HMG-CoA reductase inhibitor, estrogen, estrogen receptor agonist and/or antagonist, monoamine re-uptake inhibitor, Muscle relaxant, natriuretic peptide and its analog, natriuretic peptide remove receptor antagonist, enkephalinase inhibitor, nitric oxide donors, Non-steroid anti-inflammatory agent, N-methyl d-aspartate receptor agonist, opioid receptor agonist, di-phosphate ester enzyme level Agent, prostaglandin analogue, Prostanoid receptor agonist, renin inhibitor, selective serotonin reuptake inhibitor, sodium lead to Road blocker, sGC stimulant and activator, tricyclic antidepressants, vasopressin receptor antagonist and A combination thereof.The particular instance of these medicaments is specified in herein.
Therefore, in a still further aspect thereof, medical composition comprises the compounds of this invention, the second active agents and doctor Pharmaceutically acceptable supporting agent.3rd, the 4th active agents etc. may also comprise in the composition.In combination treatment, institute's administration The amount of the compounds of this invention and the amount of the second medicament be smaller than in monotherapy the amount of generally administration.
The compounds of this invention can mix for physically with the second active agents, thus forms the combination containing two kinds of medicaments Thing；Or each medicament may be present in out of the ordinary and different components, the while of described compositions or different time administration patient.Lift For example, conventional program and equipment can be used the compounds of this invention and the second active agents to be combined and to comprise of the present inventionization to be formed The active agents combination of compound and the second active agents.It addition, active agents can combine with pharmaceutically acceptable supporting agent, from And formed and comprise the compounds of this invention, the second active agents and the medical composition of pharmaceutically acceptable supporting agent.Real at this Executing in example, generally the component of mixing or blend composition is to produce physical mixture.It is then used by any approach as herein described With therapeutically effective amount administration physical mixture.
Or, active agents can keep independent and different before administration patient.In this embodiment, medicament administration it Before mix the most for physically, but with composition forms out of the ordinary simultaneously or in different time administration.These compositionss Can pack respectively or can be packaged in together in test kit.When in different time administration, the second medicament will generally administration this Less than 24 hours (from administration the compounds of this invention simultaneously to after being administered during any in the range of about 24 hours after bright compound Between) administration.This also referred to as sequentially offers medicine.Therefore, the compounds of this invention and another active agents can use two kinds of tablet (each work Property medicament correspondence one tablet) administration is simultaneously or sequentially administered orally, the most sequentially can refer to after administration the compounds of this invention i.e. Carve administration or in the most a certain scheduled time (1 hour the most subsequently or 3 hours subsequently) administration.It is also contemplated that the second medicament can thrown With after the compounds of this invention more than 24 hours administration in addition.Or, combination can be by different dosing way administrations, i.e. a kind of medicine Agent is administered orally administration and another medicament by sucking administration.
In one embodiment, what test kit comprised that content be enough to perform the inventive method comprises the of the compounds of this invention One dosage type low temperature and at least one comprise another dosage forms of one or more the second medicaments set forth herein.First dosage form and Two (or third) dosage form comprises the activity of the therapeutically effective amount for treating or prevent patient disease or Medical Condition altogether Medicament.
When including the second medicament, it is to exist with therapeutically effective amount so that it is logical when with the compounds of this invention administration altogether Often to produce the amount administration treating useful effect.Second medicament can in pharmaceutically acceptable salt, solvate, optical voidness vertical The forms such as body isomer.Second medicament also in prodrug forms, such as, can have the compound of the hydroxy-acid group being esterified.Cause This, herein listed by the second medicament it is intended to all these forms, and commercially available maybe can use conventional program and reagent in addition Preparation.
In one embodiment, the compounds of this invention is to combine administration, the generation of described antagonist with adenosine receptor antagonists Table example includes, but is not limited to that former times theophylline (naxifylline), sieve coughs up theophylline (rolofylline), SLV-320, tea Alkali (theophylline) and Tuo Napu theophylline (tonapofylline).
In one embodiment, the compounds of this invention is to combine administration with alpha-adrenergic aceptor antagonist, described short of money The representative example of anti-agent includes, but is not limited to doxazosin (doxazosin), prazosin (prazosin), Harnal And terazosin (terazosin) (tamsulosin).
The compounds of this invention also can be with β1-adrenergic aceptor antagonist (" β1Blocker ") combination administration.Representative β1 Blocker includes, but is not limited to acebutolol (acebutolol), alprenolol (alprenolol), amosulalol (amosulalol), arotinolol (arotinolol), atenolol (atenolol), befunolol (befunolol), times he Luo Er (betaxolol), bevantolol (bevantolol), bisoprolol (bisoprolol), bopindolol (bopindolol), bucindolol (bucindolol), bucumolol (bucumolol), bufetolol (bufetolol), fourth Furan Luo Er (bufuralol), bunitrolol (bunitrolol), bupranolol (bupranolol), Ba Buli fourth (bubridine), butofilolol (butofilolol), carazolol (carazolol), carteolol (carteolol), card Dimension Lip river, ground (carvedilol), celiprolol (celiprolol), cetamolol (cetamolol), cloranolol (cloranolol), dilevalol (dilevalol), epanolol (epanolol), esmolol (esmolol), indenes promise Lip river That (indenolol), labetalol (labetolol), levobunolol (levobunolol), mepindolol (mepindolol), metipranolol (metipranolol), metoprolol (metoprolol) (such as metoprolol succinate and Metoprolol tartrate), moprolol (moprolol), nadolol (nadolol), nadoxolol (nadoxolol), how Bi Luoer (nebivalol), nipradilol (nipradilol), oxprenolol (oxprenolol), penbutolol (penbutolol), Pei Buluoer (perbutolol), the many Luo Er of product (pindolol), practolol (practolol), the third naphthalene Luo Er (pronethalol), Propranolol (propranolol), sotalol (sotalol), Sa Feiluoer (sufinalol), tower Buddhist nun many (talindol), tertatolol (tertatolol), tilisolol (tilisolol), thiophene Lip river That (timolol), toliprolol (toliprolol), xibenolol (xibenolol) and a combination thereof.At a specific embodiment In, β1Antagonist is selected from atenolol, bisoprolol, metoprolol, Propranolol, sotalol and a combination thereof.Generally, β1 Blocker is by be enough to provide the amount administration of every dose of about 2mg to 900mg.
In one embodiment, the compounds of this invention is and β2-3 adrenergic receptor agonists combination administration, described sharp The representative example of dynamic agent includes, but is not limited to albuterol (albuterol), bitolterol (bitolterol), Fei Nuote Sieve (fenoterol), formoterol (formoterol), Yin reach Quattro (indacaterol), isoetarine (isoetharine), Levalbuterol (levalbuterol), orciprenaline (metaproterenol), pyrrole Boot sieve (pirbuterol), albuterol (salbutamol), Salmefamol (salmefamol), salmaterol (salmeterol), terbutaline (terbutaline), Wei Lanteluo (vilanterol) etc..Generally β2-adrenoceptor Agonist is by be enough to provide the amount administration of every dose of about 0.05 μ g to 500 μ g.
In one embodiment, the compounds of this invention is to combine administration with Advanced glycation endproducts (AGE) decomposition agent, The example (passing through way of illustration and not by way of limitation) of described decomposition agent include my lattice cloth (alagebrium) (or ALT-711) and TRC4149。
In another embodiment, the compounds of this invention is to combine administration, the representative of described antagonist with aldosterone antagonists Property example includes, but is not limited to eplerenone (eplerenone), spironolactone (spironolactone) and a combination thereof.Generally, Aldosterone antagonists is by be enough to provide the amount administration of about 5mg to 300mg every day.
In one embodiment, the compounds of this invention is to combine with aminopeptidase N or dipeptidyl peptidase II I inhibitor to throw With, the example (passing through way of illustration and not by way of limitation) of described inhibitor includes bestatin (bestatin) and PC18 (2- Amino-4-methyl sulphonyl butane thiol, methionine mercaptan).
The compounds of this invention also can combine administration with angiotensin converting enzyme (ACE) inhibitor.Representative ACE inhibitor Include, but is not limited to A Ku Puli (accupril), alacepril (alacepril), benazepril (benazepril), shellfish Na Pulila (benazeprilat), captopril (captopril), execute auspicious Puli (ceranapril), cilazapril (cilazapril), delapril (delapril), enalapril (enalapril), enalaprilat (enalaprilat), Fosinopril (fosinopril), fosinoprilat (fosinoprilat), imidapril (imidapril), lisinopril (lisinopril), moexipril (moexipril), Monopril Puli (monopril), not good fortune Puli (moveltipril), spray Top profit (pentopril), perindopril (perindopril), quinapril (quinapril), quinaprilat (quinaprilat), ramipril (ramipril), ramiprilat (ramiprilat), the new acetate of salad (saralasin acetate), spirapril (spirapril), temocapril (temocapril), trandolapril (trandolapril), zofenopril (zofenopril) and a combination thereof.
In a particular embodiment, ACE inhibitor is to be selected from: benazepril, captopril, enalapril, Lai Nuopu Profit, ramipril and a combination thereof.Generally, ACE inhibitor is by be enough to provide the amount administration of about 1mg to 150mg every day.At another In embodiment, the compounds of this invention is and dual function angiotensin converting enzyme/enkephalinase (ACE/NEP) inhibitor group Closing administration, the example of described medicament includes, but is not limited to: AVE-0848 ((4S, 7S, 12bR)-7-[3-methyl-2 (S)-sulfenyl Butyrylamino]-6-oxo-1,2,3,4,6,7,8,12b-octahydro pyrido [2,1-a] [2]-benzazepine-4-formic acid)； AVE-7688 (Ai Erpa is bent (ilepatril)) and its parent compound；BMS-182657 (2-[2-oxo-3 (S)-[3-benzene Base-2 (S)-sulfenyl propionamido]-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-1-base] acetic acid)；CGS-35601(N-[1- [4-methyl-2 (S)-sulfenyl valeryl amino] cyclopentylcarbonyl]-L-Trp)；Fasidotril (fasidotril)；Fasidotril Draw (fasidotrilate)；Enalaprilat；ER-32935 ((3R, 6S, 9aR)-6-[3 (S)-methyl-2 (S)-sulfenyl valeryls Amino]-5-oxo perhydrogenating thiazole also [3,2-a] azatropylidene-3-formic acid)；Lattice handkerchief QULA；MDL-101264((4S,7S, 12bR)-7-[2 (S)-(2-(N-morpholinyl) thioacetyl)-3-phenylpropionyl amino]-6-oxo-1,2,3,4,6,7,8, 12b-octahydro pyrido [2,1-a] [2] benzazepine-4-formic acid)；MDL-101287([4S-[4α,7α(R*),12bβ]]- 7-[2-(carboxymethyl)-3-phenylpropionyl amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydro pyrido [2,1-a] [2] benzene And azatropylidene-4-formic acid)；Omapatrilat；RB-105 (N-[2 (S)-(mercapto methyl)-3 (R)-benzene butyl]-ALANINE)；Mountain Handkerchief QULA；SA-898 ((2R, 4R)-N-[2-(2-hydroxy phenyl)-3-(3-mercapto radical propionyl group) Thiazolidine-4-base carbonyl]-L-benzene Base alanine)；Sch-50690 (N-[1 (S)-carboxyl-2-[N2-(methane sulfonyl)-L-lysylamino] ethyl]-L-figured silk fabrics Aminoacyl-TYR)；And may also include a combination thereof.In a particular embodiment, ACE/NEP inhibitor is to be selected from: AVE- 7688, enalaprilat, fasidotril, fasidotril draw, omapatrilat, sampatrilat and a combination thereof.
In one embodiment, the compounds of this invention is and angiotensin converting enzyme 2 (ACE2) activator or stimulant Combination administration.
In one embodiment, the compounds of this invention is to combine administration, the reality of described vaccine with Angiotensin II vaccine Example includes, but is not limited to ATR12181 and CYT006-AngQb.
In one embodiment, the compounds of this invention is to combine administration, the representative example of described anticoagulant with anticoagulant Include, but is not limited to: Coumarins (coumarins), such as warfarin (warfarin)；Heparin (heparin)；With directly solidifying Thrombin inhibitor, such as argatroban (argatroban), bivalirudin (bivalirudin), dabigatran (dabigatran) With lepirudin (lepirudin).
In another embodiment, the compounds of this invention is to combine administration with anti-diabetic medicament.Representative antidiabetic drug Agent includes injectable drug and oral active drug and a combination thereof.The example of injectable drug includes, but is not limited to insulin And insulin derivates.The example of oral active drug includes, but is not limited to: biguanide (biguanides), such as metformin (metformin)；Glycemic element (glucagon) antagonist；Alpha-Glucosidase (α-glucosidase) inhibitor, such as acarbose And miglitol (miglitol) (acarbose)；Inhibitors of dipeptidyl IV (DPP-IV inhibitor), such as Egelieting (alogliptin), De Nalieting (denagliptin), Li Nalieting (linagliptin), saxagliptin (saxagliptin), sitagliptin (sitagliptin) and vildagliptin (vildagliptin)；Meglitinide (meglitinide), such as repaglinide (repaglinide)；Oxadiazolidinedione (oxadiazolidinedione)；Sulphonyl Urea (sulfonylurea), such as chlorpropamide (chlorpropamide), glimepiride (glimepiride), glipizide (glipizide), glibenclamide (glyburide) and tolazamide (tolazamide)；Thiazolidinedione (thiazolidinedione), such as pioglitazone (pioglitazone) and rosiglitazone (rosiglitazone)；With its group Close.
In another embodiment, the compounds of this invention is to combine administration with antidiarrheal agent for treating.Representative therapy option include (but It is not limited to) oral rehydration solution (oral rehydration solution；ORS), loperamide (loperamide), fragrant Promise ester (diphenoxylate) and bismuth subsalicylate.
In another embodiment, the compounds of this invention is to combine administration with glaucoma medicament.Representative Betimol Agent includes, but is not limited to: alpha-adrenergic agonist, such as brimonidine (brimonidine)；β1-adrenoreceptor Antagonist；Surface β1Blocker, such as betaxolol, levobunolol and timolol；Carbonic anhydrase inhibitors, such as acetazolamide (acetazolamide), boolean helps amine (brinzolamide) or dorzolamide (dorzolamide)；Cholinergic agonist, such as west Dimension Merrill Lynch (cevimeline) and DMXB-anabasine (DMXB-anabaseine)；Adrenergic compounds；Miotic, such as hair Really graveoline (pilocarpine)；And prostaglandin analogue.
In another embodiment, the compounds of this invention is and lipotropism matter pharmaceutical agent combinations administration.Representative lipotropism matter medicament bag Include (but not limited to): cholesterol ester transfer protein matter inhibitor (CETP), such as peace match bent (anacetrapib), reach bent of plug And torr match bent (torcetrapib) (dalcetrapib)；Statins, as atorvastatin (atorvastatin), fluorine cut down him Spit of fland (fluvastatin), lovastatin (lovastatin), pravastatin (pravastatin), rosuvastatin And simvastatin (simvastatin) (rosuvastatin)；And a combination thereof.
In one embodiment, the compounds of this invention is to combine administration with antithrombotic agent.Representative antithrombotic agent bag Include (but not limited to): aspirin (aspirin)；Anti-platelet agents, (clopidogrel), prasugrel as more than Crow And Ticlopidine (ticlopidine) (prasugrel)；Heparin；And a combination thereof.
In one embodiment, the compounds of this invention is and also referred to as Angiotensin II 1 receptor blocker (ARB) AT1Receptor antagonist combination administration.Representative ARB includes, but is not limited to Abitesartan (abitesartan), Azilsartan (azilsartan) (the such as many Mils of Azilsartan wheat (azilsartan medoxomil)), this Losartan (benzyllosartan), Candesartan (candesartan), candesartan cilexetil are come for former times (candesartan Cilexetil), Elisartan (elisartan), Embusartan (embusartan), Yi Luo Tasosartan (enoltasosartan), Eprosartan (eprosartan), EXP3174, Fan Shatan (fonsartan), Forasartan (forasartan), lattice Losartan (glycyllosartan), Irb (irbesartan), Aesop spy woods (isoteoline), Losartan (losartan), the many sagos of wheat (medoximil), milfasartan (milfasartan), Aomei Sha Tan (olmesartan) (the such as many Mils of Olmesartan wheat (olmesartan medoxomil)), Pumi's sand difficult to understand are smooth (opomisartan), Pratosartan (pratosartan), Ripisartan (ripisartan), saprisartan (saprisartan), salad new (saralasin), Sa Meixin (sarmesin), TAK-591, Tasosartan (tasosartan), telmisartan (telmisartan), valsartan (valsartan), zolasartan (zolasartan) and its Combination.In a particular embodiment, ARB is to come for former times, Yi Puluosha selected from the many Mils of Azilsartan wheat, candesartan cilexetil Smooth, Irb, Losartan, the many Mils of Olmesartan wheat, saprisartan, Tasosartan, telmisartan, valsartan and its group Close.Exemplary salt and/or prodrug include that candesartan cilexetil is come for former times, Eprosartan Mesylate, Losartan potassium salt and Aomei Sha Tanmaiduo Mil.Generally, ARB is by be enough to provide the amount administration of every dose of about 4mg to 600mg, the most exemplary daily dosage In the range of every day 20mg to 320mg.
The compounds of this invention also can be with dual function medicament, such as AT1Receptor antagonist/enkephalinase inhibitor (ARB/ NEP) inhibitor combination administration, the example of described medicament includes, but is not limited to be described in filed in 23 days April in 2008 all genus In the U.S. Publication case No. 2008/0269305 and No. 2009/0023228 of Allegretti (Allegretti) et al. Compound, such as compound 4'-{2-ethyoxyl-4-ethyl-5-[((S)-2-sulfydryl-4-methylpentanoylamino)-methyl] miaow Azoles-1-ylmethyl }-3'-fluorine biphenyl-2-formic acid.
The compounds of this invention also can with such as Ku Erci (Kurtz) and Klein Gordon equation (Klein) (2009) hypertension research Multi-functional angiotensin receptor blocker combination administration described in (Hypertension Research) 32:826-834.
In one embodiment, the compounds of this invention is and bradykinin receptor antagonists, such as icatibant (icatibant) (HOE-140) combination administration.Expect this combination treatment can present prevention angioedema (angioedema) or The advantage of other non-wanted consequence that Kallidin I content raises.
In one embodiment, the compounds of this invention is to combine administration with calcium channel blocker.Representative calcium channel blocks Agent include, but is not limited to amlodipine (amlodipine), anipamil (anipamil), my Buddhist nun flat (aranipine), Barnidipine (barnidipine), bencyclane (bencyclane), benidipine (benidipine), bepridil (bepridil), Clentiazem (clentiazem), cilnidipine (cilnidipine), cinnarizine (cinnarizine), Your sulfur tall and erect (diltiazem), efonidipine (efonidipine), elgodipine (elgodipine), etafenone (etafenone), felodipine (felodipine), fendiline (fendiline), flunarizine (flunarizine), add Lip river Handkerchief rice (gallopamil), isradipine (isradipine), lacidipine (lacidipine), lercanidipine (lercanidipine), lidoflazine (lidoflazine), lomerizine (lomerizine), Manidipine (manidipine), Mibefradil (mibefradil), nicardipine (nicardipine), nifedipine (nifedipine), Niguldipine (niguldipine), niludipine (niludipine), nilvadipine (nilvadipine), nimodipine (nimodipine), nisoldipine (nisoldipine), nitrendipine (nitrendipine), nilvadipine (nivaldipine), perhexiline (perhexiline), prenylamine (prenylamine), Marcelo Rios spit of fland (ryosidine), semotiadil (semotiadil), terodiline (terodiline), for A Pa meter (tiapamil), Wella Handkerchief rice (verapamil) and a combination thereof.In a particular embodiment, calcium channel blocker is selected from amlodipine, benzyl generally That, diltiazem, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, Buddhist nun Not Horizon, nisoldipine, Marcelo Rios spit of fland, verapamil and a combination thereof.Generally, calcium channel blocker will be be enough to provide every dose about The amount administration of 2mg to 500mg.
In one embodiment, the compounds of this invention is and chymase inhibitor, as TPC-806 and 2-(5-Formylamino- 6-oxo-2-phenyl-1,6-dihydro-pyrimidin-1-base)-N-[{ 3,4-dioxo-1-phenyl-7-(2-pyridine radicals epoxide) }-2-heptan Base] acetamide (NK3201) combination administration.
In one embodiment, the compounds of this invention is and diuretic combinations administration.Representative diuretic includes (but not limiting In): carbonic anhydrase inhibitors, such as acetazolamide and diclofenamide (dichlorphenamide) (dichlorphenamide)；Loop diuretic (loop Diuretics), it includes that sulfamide derivative is (such as acetazolamide, ambuside (ambuside), azosemide (azosemide), bumetanide (bumetanide), butazolamide (butazolamide), chloraminophenamide (chloraminophenamide), clofenamide (clofenamide), clopamide (clopamide), clorexolone (clorexolone), disulfamide (disulfamide), ethoxzolamide (ethoxzolamide), furosemide (furosemide), mefruside (mefruside), methazolamide (methazolamide), piretanide (piretanide), torasemide (torsemide), tripamide (tripamide) and xipamide (xipamide)) and Non-sulfonamide diuretic (such as etacrynic acid (ethacrynic acid)) and other phenoxyacetic acid compound are (such as ticrynafen (tienilic acid), indacrinone (indacrinone) and quincarbate (quincarbate))；Osmotic diurtc, as sweet Dew sugar alcohol；Potassium-sparing diuretic (potassium-sparing diuretics), it include aldosterone antagonists (such as spironolactone) and Na+Channel inhibitor (such as amiloride (amiloride) and triamterene (triamterene))；Thiazine and similar thiazine Diuretic, such as althiazide (althiazide), bendroflumethiazide (bendroflumethiazide), behyd (benzylhydrochlorothiazide), benzthiazide (benzthiazide), butizide (buthiazide), chlortalidone (chlorthalidone), chlorothiazide (chlorothiazide), cyclopenthiazide (cyclopenthiazide), cyclothiazide (cyclothiazide), epitizide (epithiazide), ethiazide (ethiazide), fenquizone (fenquizone), fluorine First thiazine (flumethiazide), hydrochlorothiazide (hydrochlorothiazide), hydroflumethiazide (hydroflumethiazide), indapamide (indapamide), methyclothiazide (methylclothiazide), beautiful for gram Logical sequence (meticrane), metolazone (metolazone), paraflutizide (paraflutizide), many thiazines (polythiazide), chinethazone (quinethazone), teclothiazide (teclothiazide) and trichlormethiazide (trichloromethiazide)；And a combination thereof.In a particular embodiment, diuretic is selected from amiloride, Bu Meita Buddhist nun, chlorothiazide, chlortalidone, diclofenamide (dichlorphenamide), etacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, first diuril Piperazine, metolazone, torasemide, triamterene and a combination thereof.Diuretic will be enough to provide every day about 5mg to 50mg, more logical The often amount administration of 6mg to 25mg every day, wherein common dose is every day 6.25mg, 12.5mg or 25mg.
The compounds of this invention also can combine administration, the example bag of described inhibitor with endothelin converting enzyme (ECE) inhibitor Include (but not limited to) phosphoramidon (phosphoramidon), CGS 26303 and a combination thereof.
In a particular embodiment, the compounds of this invention is to combine administration with endothelin-receptor antagonists.In representative Skin hormone receptor antagonists includes, but is not limited to: affect the selectivity endothelin-receptor antagonists of ETA, such as avosentan Smooth (avosentan), BSF208075 (ambrisentan), Ah Qu Sentan (atrasentan), BQ-123, carat are given birth to smooth (clazosentan), darusentan (darusentan), Xi Tasaitan (sitaxentan) and Zibotentan (zibotentan)；With affect the dual endothelin receptor antagonist of Endothelin A and B receptor, such as bosentan (bosentan), ACT-064992 (macitentan), tezosentan (tezosentan).
In another embodiment, the compounds of this invention is to be also referred to as the HMG-CoA of Statins also with one or more Reductase inhibitor combination administration.Representative Statins include, but is not limited to atorvastatin, fluvastatin, lovastatin, Cut down statin (pitavastatin), pravastatin, rosuvastatin and simvastatin.
In one embodiment, the compounds of this invention is to combine administration with monoamine re-uptake inhibitor, described inhibitor Example (passing through way of illustration and not by way of limitation) includes NRI, such as atomoxetine (atomoxetine), BUP (buproprion) and BUP metabolite hydroxyl BUP, maprotiline (maprotiline), reboxetine (reboxetine) and viloxazine (viloxazine)；Selective serotonin reuptake presses down Preparation (SSRI), such as citalopram (citalopram) and citalopram metabolite Rac-Desmethylcitalopram (desmethylcitalopram), dapoxetine (dapoxetine), according to ground Pulan (escitalopram) (such as depend on general Herba Chlorophyti hydrochlorate), fluoxetine (fluoxetine) and fluoxetine demethyl metabolite Norfluoxetine (norfluoxetine), fluorine Fu Shaming (fluvoxamine) (such as fluvoxamine maleate), paroxetine (paroxetine), Sertraline And Sertraline metabolite Desmethylsertraline (demethylsertraline) (sertraline)；On dual serotonin-nor-kidney Parathyrine reuptake inhibitor (SNRI), such as bicifadine (bicifadine), duloxetine (duloxetine), midalcipran (milnacipran), nefazodone (nefazodone) and venlafaxine (venlafaxine)；And a combination thereof.
In another embodiment, the compounds of this invention is to combine administration, the reality of described muscle relaxant with muscle relaxant Example includes, but is not limited to: carisoprodol (carisoprodol), chlorzoxazone (chlorzoxazone), ring benzene are pricked flat (cyclobenzaprine), diflunisal (diflunisal), metaxalone (metaxalone), methocarbamol And a combination thereof (methocarbamol).
In one embodiment, the compounds of this invention is to combine administration, described natriuretic peptide or class with natriuretic peptide or the like Include, but is not limited to like the example of thing: carperitide (carperitide), CD-NP (Neil therapy company (Nile Therapeutics)), CU-NP, Nesiritide (nesiritide), PL-3994 (Palatin Technologies Inc. (Palatin Technologies, Inc.)), ularitide (ularitide), Sen Deli peptide (cenderitide) and coulee (Ogawa) etc. Compound described in people (2004) journal of biological chemistry (J.Biol.Chem.) 279:28625-31.These compounds are also referred to as Natriuretic peptide receptor-A (NPR-A) agonist.In another embodiment, the compounds of this invention is to remove receptor (NPR-with natriuretic peptide C) antagonist, such as SC-46542, cANF (4-23) and AP-811 (Wei Er (Veale) (2000) bioorganic chemistry and medicineization Learn communication (Bioorg Med Chem Lett) 10:1949-52) combination administration.For example, when with nep inhibitor Sai Aofen During combination, AP-811 has shown that synergism, and (Wegener (Wegner) (1995) is clinical and tests hypertension (Clin.Exper.Hypert.)17:861-876)。
In another embodiment, the compounds of this invention is to combine administration with enkephalinase (NEP) inhibitor.Representative NEP Inhibitor includes, but is not limited to: AHU-377；Candoxatril；Candoxatrilat；Dexecadotril (dexecadotril) ((+)-N-[2 (R)-(thioacetyl methyl)-3-PHENYLPROPIONYL] glycine benzene methyl)；CGS-24128 (3-[3-(biphenyl-4-base)-2- (phosphonomethyl amino group) propionamido] propanoic acid)；CGS-24592 ((S)-3-[3-(biphenyl-4-base)-2-((phosphonomethyl) ammonia Base) propionamido] propanoic acid)；CGS-25155 (N-[9 (R)-(thioacetyl methyl)-10-oxo-1-azacyclo-decyl-2 (S)-base Carbonyl]-4 (R)-OH-L-proline benzene methyls)；It is described in Heppworth (Hepworth) et al. (Pfizer (Pfizer Inc.) 3-(the 1-carbamyl cyclohexyl) propanoic derivatives in WO 2006/027680)；JMV-390-1 (2 (R)-benzene first Base-3-(N-hydroxycarbamoyl) propiono-L-isoleucyl--L-Leu)；Ecadotril (ecadotril)；Phosphono two Peptide；In bent Sai Aofen (retrothiorphan)；RU-42827 (2-(mercapto methyl)-N-(4-pyridine radicals) hydrocinnamamide)；RU- 44004 (N-(4-morpholinyl)-3-phenyl-2-(butylthiomethyl) propionic acid amide .s)；SCH-32615 ((S)-N-[N-(1-carboxyl-2-benzene Ethyl)-L-phenylalanyl]-Beta-alanine) and its prodrug SCH-34826 ((S)-N-[N-[1-[[(2,2-dimethyl-1, 3-dioxolanes-4-base) methoxyl group] carbonyl]-2-phenethyl]-L-phenylalanyl]-Beta-alanine)；Sai Luofei (sialorphin)；SCH-42495 (N-[2 (S)-(Acetylsulfanyl methyl)-3-(2-aminomethyl phenyl) propiono]-L-egg ammonia Acetoacetic ester)；This Lip river non-(spinorphin)；SQ-28132 (N-[2-(mercapto methyl)-1-oxo-3-phenyl propyl] bright ammonia Acid)；SQ-28603 (N-[2-(mercapto methyl)-1-oxo-3-phenyl propyl]-Beta-alanine)；SQ-29072 (7-[[2-(mercapto Ylmethyl)-1-oxo-3-phenyl propyl] amino] enanthic acid)；Sai Aofen and its prodrug racecadotril (racecadotril)； UK-69578 (cis-4-[[[1-[2-carboxyl-3-(2-methoxy ethoxy) propyl group] cyclopenta] carbonyl] amino] hexamethylene first Acid)；UK-447,841 (2-{1-[3-(4-chlorphenyl) propyl group carbamyl]-cyclopentyl-methyl }-4-methoxyl group butanoic acid)；UK- 505,749 ((R)-2-methyl-3-{1-[3-(2-methylbenzothiazole-6-base) propyl group carbamyl] cyclopenta } propanoic acid)；5- Biphenyl-4-base-4-(3-carboxypropanoyl amino)-2 methyl valeric acid and 5-biphenyl-4-base-4-(3-carboxypropanoyl amino)- 2 methyl valeric acid ethyl ester (WO 2007/056546)；The WO of Kai De (Khder) et al. (Novartis Co., Ltd (Novartis AG)) Daglutril (daglutril) [(3S, 2'R)-3-{1-[2'-(ethoxy carbonyl)-4'-benzene fourth described in 2007/106708 Base]-ring amyl-1-carbonylamino }-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzazepine-1-acetic acid]；And a combination thereof.? In one specific embodiment, nep inhibitor be selected from AHU-377, candoxatril, candoxatrilat, CGS-24128, phosphoramidon, SCH-32615, SCH-34826, SQ-28603, Sai Aofen and a combination thereof.In a particular embodiment, nep inhibitor is tool There is the compound as endothelin converting enzyme (ECE) Yu the inhibitor activity of NEP, such as daglutril or CGS-26303 ([N-[2-(biphenyl-4-base)-1 (S)-(1H-TETRAZOLE-5-base) ethyl] amino] methylphosphonic acid).It is used as other dual work With property ECE/NEP compound.Nep inhibitor by be enough to provide the amount administration of about 20mg to 800mg every day, wherein typical case's every day Dosage every day 50mg to 700mg, be more typically every day 100mg to 600mg or 100mg to 300mg in the range of.
In one embodiment, the compounds of this invention is to combine administration, the example bag of described donor with nitric oxide donors Include (but not limited to) nicorandil (nicorandil)；Organic nitrates, such as pentaerythritol tetranitrate；With sydnone imines (sydnonimine), such as linsidomine (linsidomine) and molsidomine (molsidomine).
In another embodiment, the compounds of this invention right and wrong non-steroidal anti-inflammatory agent (NSAID) combination administration.Representative NSAID includes, but is not limited to: acemetacin (acemetacin), aspirin (acetyl salicylic acid), Ah Chlorine sweet smell acid (alclofenac), alminoprofen (alminoprofen), amfenac (amfenac), Amiprilose (amiprilose), A Moxi woods (amoxiprin), anirolac (anirolac), azapropazone (apazone), A Zha Acetone (azapropazone), benorylate (benorilate), benzene ibuprofen (benoxaprofen), benzene piperazine are grand (bezpiperylon), broperamole (broperamole), bucloxic acid (bucloxic acid), carprofen (carprofen), ring Clorindanol (clidanac), diclofenac (diclofenac), diflunisal, diftalone (diftalone), enolicam (enolicam), etodolac (etodolac), etoricoxib (etoricoxib), fenbufen (fenbufen), fenclofenac (fenclofenac), fenclozic acid (fenclozic acid), fenoprofen (fenoprofen), fentiazac (fentiazac), feprazone (feprazone), flufenamic acid (flufenamic acid), flufenisal (flufenisal), Fluprofen (fluprofen), flurbiprofen (flurbiprofen), furofenac (furofenac), ibufenac (ibufenac), ibuprofen (ibuprofen), indomethacin (indomethacin), indoprofen (indoprofen), Aesop Gram acid (isoxepac), isoxicam (isoxicam), ketoprofen (ketoprofen), ketorolac (ketorolac), the non-miaow in Lip river Azoles (lofemizole), lornoxicam (lornoxicam), meclofenamic acid salt (meclofenamate), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), meloxicam (meloxicam), U.S. husky amine (mesalamine), miroprofen (miroprofen), mofebutazone (mofebutazone), nabumetone (nabumetone), Naproxen (naproxen), niflumic acid (niflumic acid), oxaprozin (oxaprozin), flat sour (oxpinac), hydroxyl Cloth ancestor (oxyphenbutazone), bute (phenylbutazone), piroxicam (piroxicam), pirprofen (pirprofen), pranoprofen (pranoprofen), salsalate (salsalate), sudoxicam (sudoxicam), willow Nitrogen sulfapyridine (sulfasalazine), sulindac (sulindac), suprofen (suprofen), tenoxicam (tenoxicam), tiopinac (tiopinac), tiaprofenic acid (tiaprofenic acid), sulfur ibuprofen (tioxaprofen), tolfenamic acid (tolfenamic acid), tolmetin (tolmetin), triflumidate (triflumidate), zidometacin (zidometacin), zomepirac (zomepirac) and a combination thereof.At a particular implementation In example, NSAID is selected from etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam, Nabumetone Life, oxaprozin, piroxicam and a combination thereof.
In one embodiment, the compounds of this invention is to throw with the combination of N-methyl d-aspartic acid (NMDA) receptor antagonist With, the example (passing through way of illustration and not by way of limitation) of described antagonist includes amantadine (amantadine), dextro-methorphan (dextromethorphan), dextropropoxyphene (dextropropoxyphene), ketamine (ketamine), ketobemidone (ketobemidone), memantine (memantine), methadone (methadone) etc..
In another embodiment, the compounds of this invention is and opioid receptor agonist (also referred to as opioid Analgesic) combination administration.Representative opioid receptor agonist includes, but is not limited to: buprenorphine (buprenorphine), butorphanol (butorphanol), codeine (codeine), paracodin (dihydrocodeine), fentanyl (fentanyl), hydrocodone (hydrocodone), hydromorphone (hydromorphone), levallorphan (levallorphan), levorphanol (levorphanol), Pethidine (meperidine), methadone, morphine (morphine), nalbuphine (nalbuphine), nalmefene (nalmefene), allyl Morphine (nalorphine), naloxone (naloxone), naltrexone (naltrexone), nalorphine (nalorphine), oxygen Can ketone (oxycodone), oxydimorphine ketone (oxymorphone), Pentazocine (pentazocine), propoxyhene (propoxyphene), tramadol (tramadol) and a combination thereof.In certain embodiments, opioid receptor agonist is Selected from codeine, paracodin, hydrocodone, hydromorphone, morphine, oxycodone, oxydimorphine ketone, tramadol and a combination thereof.
In a particular embodiment, the compounds of this invention is and phosphodiesterase (PDE) inhibitor, PDE-specifically V inhibitor combination administration.Representative PDE-V inhibitor includes, but is not limited to avanaphil (avanafil), that is non-on sieve ground (lodenafil), meter Luo Nafei (mirodenafil), sldenafil (sildenafil)Tadalafil (tadalafil)Vardenafil (vardenafil)With excellent ground that non-(udenafil).
In another embodiment, the compounds of this invention is and prostaglandin analogue (also referred to as prostanoid (prostanoids) or prostacyclin (prostacyclin) analog) combination administration.Representative prostaglandin analogue includes (but not limited to) Beraprost Sodium (beraprost sodium), bimatoprost (bimatoprost), epoprostenol (epoprostenol), iloprost (iloprost), latanoprost (latanoprost), tafluprost (tafluprost), travoprost (travoprost) and UT-15 (treprostinil), wherein bimatoprost, Latanoprost and tafluprost are especially relevant.
In another embodiment, the compounds of this invention is to combine administration, described agonist with Prostanoid receptor agonist Example include, but is not limited to bimatoprost, latanoprost, travoprost etc..
The compounds of this invention also can with renin inhibitor combine administration, the example of described inhibitor include, but is not limited to Ah Li Jilun (aliskiren), enalkiren (enalkiren), remikiren (remikiren) and a combination thereof.
In another embodiment, the compounds of this invention is to throw with selective serotonin reuptake inhibitor (SSRI) combination With.Representative SSRI includes, but is not limited to: citalopram and citalopram metabolite Rac-Desmethylcitalopram, dapoxetine, depend on Pulan, ground (such as according to Pulan, ground oxalates), fluoxetine and fluoxetine demethyl metabolite Norfluoxetine, fluvoxamine (fluorine volt Husky bright maleate), paroxetine, Sertraline and Sertraline metabolite Desmethylsertraline and a combination thereof.
In one embodiment, the compounds of this invention is and 5-HT1DSerotonin receptor agonist combination administration, described excitement The example (passing through way of illustration and not by way of limitation) of agent includes Pu Tan (triptans), as almotriptan (almotriptan), Avitriptan (avitriptan), eletriptan (eletriptan), frovatriptan (frovatriptan), that draw song Pu Tan (naratriptan), rizatriptan (rizatriptan), sumatriptan (sumatriptan) and Zolmitriptan (zolmitriptan)。
In one embodiment, the compounds of this invention is to combine administration, the example of described blocker with sodium channel blockers (passing through way of illustration and not by way of limitation) includes carbamazepine (carbamazepine), fosphenytoin (fosphenytoin), draws Not triazine (lamotrigine), lignocaine (lidocaine), mexiletine (mexiletine), oxcarbazepine (oxcarbazepine), phenytoin (phenytoin) and a combination thereof.
In one embodiment, the compounds of this invention is to throw with sGC stimulant or activator combination With, the example of described stimulant or activator includes, but is not limited to A Taxi piperazine (ataciguat), Li Aoxi piperazine And a combination thereof (riociguat).
In one embodiment, the compounds of this invention is to combine administration with tricyclic antidepressants (TCA), and described three rings are anti-to be pressed down The example (passing through way of illustration and not by way of limitation) of strongly fragrant dose includes amitriptyline (amitriptyline), amitriptylinoxide (amitriptylinoxide), butriptyline (butriptyline), clomipramine (clomipramine), demexiptiline (demexiptiline), desipramine (desipramine), dibenzepin (dibenzepin), dimetacrine (dimetacrine), dosulepin (dosulepin), doxepin (doxepin), imipramine (imipramine), imipraminoxide (imipraminoxide), love handkerchief bright (lofepramine), melitracen (melitracen), metapramine (metapramine), nitre sand Xiping (nitroxazepine), nortriptyline (nortriptyline), noxiptiline (noxiptiline), pipofezine (pipofezine), propizepine (propizepine), protriptyline (protriptyline), quinupramine (quinupramine) and a combination thereof.
In one embodiment, the compounds of this invention is and vasopressin receptor antagonist-combination administration, described antagonism The example (passing through way of illustration and not by way of limitation) of agent includes conivaptan (conivaptan) and tolvaptan (tolvaptan)。
Second therapeutic agent of combination also can be useful in other combination treatment carried out with the compounds of this invention.Citing comes Saying, the compounds of this invention can lead to diuretic and ARB or calcium channel blocker and ARB or diuretic and ACE inhibitor or calcium Road blocker and Statins combination.Particular instance includes ACE inhibitor enalapril (in maleate form) and diuretic hydrogen The combination of chlorothiazide, it is at trade markLower sale；Or calcium channel blocker amlodipine (in benzenesulfonate salt forms) with The combination of ARB Olmesartan (in wheat many Mils prodrug forms)；Or the combination of calcium channel blocker and Statins, all these realities Example the most all can be used together with the compounds of this invention.Such as α2-3 adrenergic receptor agonists and vasopressin receptor antagonism Other therapeutic agent of agent also can be useful in combination treatment.Exemplary α2-3 adrenergic receptor agonists includes clonidine (clonidine), dexmedetomidine (dexmedetomidine) and guanfacine (guanfacine).
The representative medical composition of the following composite explanation present invention.
For the Exemplary hard gelatine capsule of administration is administered orally
Fully blend the compounds of this invention (50g), the lactose of 440g spray drying and 10g magnesium stearate.Then by gained Compositions loads in hard gelatine capsule (every capsule 500mg compositions).Or, fully blend the compounds of this invention (20mg) with Starch (89mg), microcrystalline Cellulose (89mg) and magnesium stearate (2mg).Then mixture is made to cross No. 45 U.S. sieve of screen size And load (every capsule 200mg compositions) in hard gelatine capsule (U.S.sieve).
Or, the most fully blend and process the compounds of this invention (30g), the second medicament (20g), 440g spray dried Dry lactose and 10g magnesium stearate.
For the exemplary gelatine capsule composite of administration is administered orally
Fully blend the compounds of this invention (100mg) and Polysorbate 80 (50mg) and starch (250mg).Then fill this blend into (every capsule 400mg compositions) in gelatine capsule.Or, fully blend chemical combination of the present invention Thing (70mg) and the second medicament (30mg) and Polysorbate 80 (50mg) and starch (250mg), and Gained mixture is loaded in gelatine capsule (every capsule 400mg compositions).
Or, fully blend the compounds of this invention (40mg) and microcrystalline Cellulose (Avicel PH 103；259.2mg) and Magnesium stearate (0.8mg).Then (every capsule 300mg group in gelatine capsule (No. 1 size, white, opaque) is filled this blend into Compound).
For the exemplary tablet formulations of administration is administered orally
Make the compounds of this invention (10mg), starch (45mg) and microcrystalline Cellulose (35mg) cross No. 20 U.S. sieve of screen size and It is sufficiently mixed.Consequent granule is dried at 50 DEG C to 60 DEG C and crosses No. 16 U.S. sieve of screen size.Make polyvinylpyrrolidine The solution (4mg 10% solution in sterilized water) of ketone and carboxymethyl starch sodium (4.5mg), magnesium stearate (0.5mg) and Talcum (1mg) mixing, and then make this mixture cross No. 16 U.S. sieve of screen size.Then by carboxymethyl starch sodium, magnesium stearate and cunning Stone adds in granule.After blending, pressing mixt on tablet machine, obtain the tablet of weight 100mg.
Or, fully blend the compounds of this invention (250mg) and microcrystalline Cellulose (400mg), smoke-like silicon dioxide (10mg) with stearic acid (5mg).Then pressing mixt is to form tablet (every 665mg compositions).
Or, fully blend the compounds of this invention (400mg) and corn starch (50mg), cross-linked carboxymethyl cellulose sodium (25mg), lactose (120mg) and magnesium stearate (5mg).Then pressing mixt is to form single indentation tablet (every 600mg group Compound).
Or, fully blend the compounds of this invention (100mg) and corn starch (100mg) with gelatin (20mg) aqueous solution. Drying composite and grind to form fine powder.Then microcrystalline Cellulose (50mg) and magnesium stearate (5mg) is made to blend with gelatin composite, Granulation and compacting gained mixture are to form tablet (every 100mg the compounds of this invention).
For the exemplary suspension formulations of administration is administered orally
Mixing following ingredients is to form the suspension that every 10mL suspension contains 100mg the compounds of this invention:
For the exemplary fluids composite of administration is administered orally
The liquid formulation being suitable for is to buffer containing buffer based on carboxylic acid, such as citrate, lactate and maleate The composite of solution.For example, the compounds of this invention (it can mix in advance) and 100mM ammonium citrate buffer are made with DMSO Blend and adjust pH value to pH 5, or blend with 100mM citric acid solution and adjustment pH value is to pH 2.These solution may also include Lyotropy excipient, as cyclodextrin, such as solution can include 10 weight % HP-β-CD.
Other composite being suitable for includes the 5%NaHCO with or without cyclodextrin3Solution.
For the exemplary injectable composite by injecting administration
Blend the compounds of this invention (0.2g) and 0.4M sodium acetate buffer solution (2.0mL).Use 0.5N hydrochloric acid if desired The pH value of aqueous solution or 0.5N sodium hydrate aqueous solution adjustment gained solution is to pH 4, and is subsequently added into enough water for injection to carry Cumulative volume for 20mL.Mixture then filters to provide the nothing be suitable to by injecting administration through sterilizing filter (0.22 micron) Bacterium solution.
For the exemplary composition by sucking administration
The compounds of this invention (0.2mg) through micronized and then blends with lactose (25mg).Then by this blended mixing Compound loads gelatin and sucks in cartridge case.Use the inclusions of such as Diskus administration cartridge case.
Or, make micronized the compounds of this invention (10g) be scattered in by lecithin (0.2g) is dissolved in mineral In the solution prepared in matter water (200mL).Be spray-dried gained suspension and then carry out micronized with formed comprise average Diameter is less than about the micronized composition of the particle of 1.5 μm.Then micronized composition is loaded the 1,1,1,2-containing pressurization In the metered-dose inhaler cartridge case of tetrafluoroethane, this explosive payload be enough to provide every dose of about 10 μ g to about when by inhaler administration 500 μ g the compounds of this invention.
Or, the compounds of this invention (25mg) is dissolved in the isotonic saline solution (125mL) through Citrate buffer (pH 5) In.Stir mixture and carry out sonicated until compound dissolution.Check the pH value of solution and as necessary by being slowly added to 1N NaOH aqueous solution is adjusted to pH 5.Use sprayer device administration solution can provide every dose of about 10 μ g to about 500 μ g this Bright compound.
Example
There is provided following preparation and example so that only certain embodiments of the present invention to be described.But, unless specifically indicated, otherwise these Specific embodiment is not intended to limit the scope of the present disclosure in any way.Unless otherwise instructed, otherwise following abbreviations has following Implication, and other abbreviation any that is used herein and that do not defined all has its standard and generally acknowledges implication:
AcOH acetic acid
Cbz benzene methoxycarbonyl group (-C (O) O-benzyl)
DCM dichloromethane (dichloromethane or methylene chloride)
DIPEA N, N-diisopropylethylamine
DMF N,N-dimethylformamide
Dnp dinitrophenyl group
EDCI N-(3-dimethylaminopropyl)-N "-ethylcarbodiimine
EtOAc ethyl acetate
EtOH ethanol
HATU hexafluorophosphoric acid N, N, N', N'-tetramethyl-O-(7-azepine benzo triazol-1-yl) urea
HEPES 4-(2-ethoxy)-1-piperazine ethanesulfonic acid
HOBt is hydrated I-hydroxybenzotriazole
Mca (ayapanin-4-base) acyl group
MeCN acetonitrile
MeOH methanol
Pd(PPh3)4Tetrakis triphenylphosphine palladium (0)
DPP-Pd diphenylphosphine based on silicon dioxide palladium (II) catalyst
TFA trifluoroacetic acid
THF oxolane
Unless otherwise instructed, otherwise all substances, as reagent, initial substance and solvent are all purchased from commercial suppliers (such as west Ge Ma-aldrich company (Sigma-Aldrich), Reed that-Derham Trading Ltd. of good fortune an outpost of the tax office (Fluka Riedel-de) Deng) and the most i.e. use.
Unless otherwise instructed, otherwise react and carry out in a nitrogen atmosphere.Reaction progress is by thin layer chromatography (TLC), divides Analysis type high performance liquid chromatography (analytical type HPLC) and mass spectrum are monitored, and its details are given in particular instances.Analytical type The solvent used in HPLC is as follows: solvent orange 2 A is 98%H2O/2%MeCN/1.0mL/L TFA；Solvent B is 90%MeCN/10% H2O/1.0mL/L TFA。
Reactant is processed as described in clear and definite in the most each preparation；Generally by extraction and other purification process, such as temperature Dependency and solvent dependant crystallization and precipitation carry out purification reaction mixture.Additionally, reactant mixture is by generally using Microsorb C18 and Microsorb BDS column packing and conventional eluant are prepared type HPLC and carry out in addition general purification 's.Reaction progress is generally measured by liquid chromatography mass (LCMS).The sign of isomer is to pass through nuclear Overhauser effect Spectrum analysis (Nuclear Overhauser effect spectroscopy, NOE) is carried out.By mass spectrum and1H-NMR spectrum Carry out the sign of product routinely.NMR is measured, sample is dissolved in deuterated solvents (CD3OD、CDCl3Or DMSO- d6In), and obtain under the conditions of standard sight with Varian Gemini 2000 instrument (400MHz)1H-NMR spectrum.Generally make In order to Applied Biosystems (Foster city, California (Foster City, CA)) model API 150EX instrument Or the electron spray that Agilent (Palo Alto, CA (Palo Alto, CA)) model 1200LC/MSD instrument is carried out Ionization method (ESMS) carries out the mass spectrum of compound and differentiates.
Preparation 1
[(R)-1-(the chloro-benzyl of 2-)-2-cyano-2-hydroxy-ethyl]-carbamic acid benzene methyl
To (R)-2-amino-3-(the chloro-phenyl of the 2-)-propanoic acid (100.0g, 0.5mol) suspension in water (1L) at 0 DEG C Liquid is added dropwise over 4N NaOH aqueous solution (125mL).Then, N-(benzyloxy carbonyloxy group) succimide is disposably added (125.0g, 0.5mol) solution in acetone (300mL).By adding 3N NaOH aqueous solution, the pH value of mixture is maintained 8 to 9.Stirring mixture after 4 hours, is adjusted to 1 with 6N HCl by pH value, and with EtOAc (2 × 500mL) extraction mixture. The extract merged 1N HCl (2 × 500mL) washs, through anhydrous Na2SO4It is dried and concentrates, obtain the change of white solid, shaped Compound (1) (155.0g).
EDCI (50.6g, 264 μ is added in the compound (1) (80.0g, 240 μm ol) solution in DCM (500mL) Mol), HOBt (35.6g, 264 μm ol), N, O-dimethyl hydroxylamine hydrochloride (51.5g, 528 μm ol) and triethylamine (111mL, 790μmol).It is stirred at room temperature mixture overnight.Then, mixture is respectively with 2N HCl (3 × 500mL) and NaHCO3Saturated Aqueous solution (3 × 500mL) washs.Organic layer is through anhydrous Na2SO4It is dried and concentrates, obtain the compound (2) in yellow oil (71.0g)。
To LiAlH at-20 DEG C4(7.2g, 188 μm ol) suspension in THF (800mL) is added dropwise over compound (2) (71.0g, the 188 μm ol) solution in THF (200mL).Mixture is stirred 2 hours at-20 DEG C.Then, reactant is used 1N HCl cancellation carefully.Mixture EtOAc (2 × 600mL) extracts, and the extract merged is through anhydrous Na2SO4Be dried and Concentrating, obtain compound (3) (59.0g), it the most directly uses without further purification.
NaHSO is added in the compound (3) (59.0g, 188 μm ol) solution in THF (500mL)3Aqueous solution (19.5g is in 500mL water), and stir mixture overnight at 0 DEG C.Add NaCN (9.2g, 188 μm ol), and gained is mixed Compound stirs 3 hours.Mixture EtOAc (2 × 500mL) extracts, and the extract merged is through anhydrous Na2SO4It is dried and dense Contracting, obtains title compound (64.0g), and it the most directly uses without further purification.
Preparation 2
(2R, 3R)-3-amino-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid methyl ester
By [(R)-1-(the chloro-benzyl of 2-)-2-cyano-2-hydroxy-ethyl]-carbamic acid benzene methyl (55.0g, 157 μ Mol) the mixture heated overnight under reflux in dioxane (300mL) and 6N HCl (300mL).Under reduced pressure remove molten Agent, and residue is dissolved in 3N HCl-MeOH solution.Gained mixture is refluxed 4 hours and under reduced pressure removes solvent. Residue is absorbed in EtOAc (500mL) and NaHCO3In aqueous solution (500mL).Separate organic layer, through anhydrous Na2SO4It is dried And concentrate, obtain the mixture of title compound and its (R, S)-isomer, make described mixture stand flash column chromatography (DCM: MeOH=100:1 to 50:1), obtain title compound (8.1g).
1H NMR(CDCl3): δ 7.37 (m, 1H), 7.22 (m, 3H), 4.30 (d, J=3.3Hz, 1H), 3.80 (s, 3H), 3.51(m,1H),2.96(m,1H),2.71(m,1H),2.06(br s,2H)。MS(m/z):244[M+H]+。
Preparation 3
(2R, 3R)-3-amino-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid ethyl ester
By [(R)-1-(the chloro-benzyl of 2-)-2-cyano-2-hydroxy-ethyl]-carbamic acid benzene methyl (64.0g, 188 μ Mol) the mixture heated overnight under reflux in dioxane (300mL) and 6N HCl (300mL).Under reduced pressure remove molten Agent, and residue is dissolved in 3N HCl-EtOH solution.Gained mixture is refluxed 4 hours and under reduced pressure removes solvent. Residue is absorbed in EtOAc (500mL) and NaHCO3In aqueous solution (500mL).Separate organic layer, through anhydrous Na2SO4It is dried And concentrate, obtain the mixture of title compound and its (R, S)-isomer, make described mixture stand flash column chromatography (DCM: MeOH=100:1 to 50:1), obtain title compound (9.7g).
1H NMR(CDCl3): δ 7.37 (m, 1H), 7.22 (m, 3H), 4.25 (m, 3H), 3.50 (s, 1H), 2.97 (d, J= 10.8Hz, 1H), 2.74 (t, J=11.4Hz, 1H), 2.06 (br s, 2H), 1.35 (t, J=7.1Hz, 3H).MS(m/z):258 [M+H]+。
Example 1
2-{2-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-pyridin-4-yl }- Benzoic acid (R 1 =-OH；R 41 =H)
By 4-Bromopicolinic acid methyl ester (167mg, 772 μm ol, 1.0 equivalents) and 2-tert-butoxycarbonyl phenyl boric acid frequency which Alcohol ester (282mg, 927 μm ol, 1.2 equivalents) is mixed in toluene (1.1mL).Sequentially add MeOH (409 μ L) and predissolve in K in water (202 μ L)2CO3(214mg, 1.5mmol, 2.0 equivalent).Stirring mixture, and reaction vessel is added a cover, it is placed in vacuum Down and purify with nitrogen.Add Pd (PPh3)4(89.2mg, 77.2 μm ol).Container is added a cover again and at 110 DEG C, heats 50 Minute.Remove organic layer, and vaporising under vacuum product.(1.5mL, 2.0 work as addition THF (3mL) and 1M NaOH aqueous solution Amount), and stir the mixture for 2 hours.Add EtOAc, and use saturated NH4Cl acidifying mixture.Extraction organic layer, is dried and steams Send out, obtain 4-(2-tert-butoxycarbonyl-phenyl)-pyridine-2-formic acid.
By 4-(2-tert-butoxycarbonyl-phenyl)-pyridine-2-formic acid (30mg, 0.1mmol, 1.0 equivalent) and (2R, 3R)- 3-amino-4-(2 chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (16.8mg, 65.1 μm ol, 1.0 equivalents) and DIPEA (52.4 μ L, 3.0 equivalents) and HATU (26.7mg, 70.2 μm ol, 0.7 equivalent) and DCM (0.8mL) merging, and it is mixed to be stirred at room temperature gained Compound 45 minutes.The saturated NH of reactant4Cl cancellation, and product extracted with DCM, be dried and evaporate, obtain 2-{2-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyridin-4-yl } the tertiary fourth of-benzoic acid Ester.
By 2-{2-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyrrole Pyridine-4-base }-t-butyl perbenzoate (104mg, 192 μm ol, 1.0 equivalents) merges with 1:1TFA/DCM (each 1mL), and by gained Mixture stirs 1 hour.Evaporation solvent, and add THF (3mL) and 1M NaOH aqueous solution (577 μ L, 3.0 equivalents), and by institute Obtain mixture to stir 2 hours.Evaporation solvent, and add AcOH (2mL).Then product pass through preparation HPLC purification, obtain in The title compound (2.4mg, 96% purity) of tfa salt form.C23H19ClN2O6MS m/z [M+H]+Value of calculation: 455.09； Experiment value: 455.
2-{2-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyridine- 4-yl }-ethyl benzoate (R 1 =-OCH 2 CH 3 ；R 41 =-CH 2 CH 3 )
By 4-bromopyridine-2-formic acid (93.9mg, 465 μm ol, 1.0 equivalents) and (2R, 3R)-3-amino-4-(chloro-benzene of 2- Base)-2-hydroxy-butyric acid ethyl ester (120mg, 465 μm ol, 1.0 equivalents) and DIPEA (434 μ L) and HATU (177mg, 465 μm ol, 1.0 equivalents) it is incorporated in DCM (4mL) and is stirred at room temperature 45 minutes.The saturated NaHCO of reactant3Cancellation, and extract with DCM Take, be dried and evaporate, obtaining (2R, 3R)-3-[(4-bromo-pyridine-2-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-2-hydroxyl-fourth Acetoacetic ester.By this crude product and 2-(4,4,5,5-tetramethyl-1,3,2-dioxa boron penta ring-2-base) ethyl benzoate (154mg, 558 μm ol, 1.2 equivalents) and toluene (540 μ L) mix.Sequentially add EtOH (0.3mL) and predissolve in water (0.1mL) K in2CO3(128mg, 930 μm ol, 2.0 equivalents).Stirring mixture, and reaction vessel is added a cover, it is placed under vacuum And purify with nitrogen.Add Pd (PPh3)4(53.7mg, 46.5 μm ol).Container is added a cover again and heats 30 points at 100 DEG C Clock.Retain organic layer, and product vaporising under vacuum, be then used by preparation HPLC purification, obtain the title in tfa salt form Compound (30mg, 97% purity).C27H27ClN2O6MS m/z [M+H]+Value of calculation: 511.16；Experiment value: 512.2.
2-{2-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyridine- 4-yl }-benzoic acid (R 1=-OCH2CH3；R41 =H)
By thick 2-{2-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]- Pyridin-4-yl }-ethyl benzoate is dissolved in DCM/TFA (each 0.3mL) and stirs 2 hours.Evaporation solvent, and product use Preparation HPLC purification, obtains the title compound (75mg, 97% purity) in tfa salt form.C25H23ClN2O6MS m/z [M+H]+Value of calculation: 483.12；Experiment value: 483.
Example 2
Follow the program described in present example and replace suitable initial substance and reagent, with parent compound form or with The preparation of tfa salt form has a compound of Formulas I c:
1. 2-{2-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-6-methyl- Pyridin-4-yl }-benzoic acid (tfa salt)
2. 2-{4-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-pyridine-2- Base }-benzoic acid (tfa salt)
3. 2-{4-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyrrole Pyridine-2-base }-ethyl benzoate (tfa salt)
4. 2-{4-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-6-methyl- Pyridine-2-base }-benzoic acid (tfa salt)
5. 2-{5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-pyridine-3- Base }-benzoic acid (tfa salt)
6. 2-{5-[(1R, 2R)-1-(the chloro-benzyl of 2-)-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl]-pyrrole Pyridine-3-base }-benzoic acid (tfa salt)
7. 2-{5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-2-hydroxyl- Pyridin-3-yl }-benzoic acid (tfa salt)
8. 2-{5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-pyridine-2- Base }-benzoic acid (tfa salt)
9. 2-{5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl] the chloro-pyrrole of-3- Pyridine-2-base }-benzoic acid (tfa salt)
10. 2-{5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl] the fluoro-pyrrole of-3- Pyridine-2-base }-benzoic acid (tfa salt)
11. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(3-hydroxyl-isoxazole-5-carbonyl)-amino]-butanoic acid (tfa salt)
12. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [3-(the chloro-phenyl of 2-)-isoxazole-5-carbonyl]-amino }-2-hydroxyl Base-butanoic acid (tfa salt)
13. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [3-(the chloro-phenyl of 3-)-isoxazole-5-carbonyl]-amino }-2-hydroxyl Base-butanoic acid (tfa salt)
14. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [3-(the chloro-phenyl of 4-)-isoxazole-5-carbonyl]-amino }-2-hydroxyl Base-butanoic acid (tfa salt)
15. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [5-(the chloro-phenyl of 2-)-isoxazole-3-carbonyl]-amino }-2-hydroxyl Base-butanoic acid (tfa salt)
16. (2R, 3R)-3-{ [2-(the fluoro-benzyl of the chloro-2-of 4-)-3-oxo-2,3-dihydro-isoxazole-5-carbonyl]-ammonia Base }-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid (tfa salt)
17. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [2-(2,3-bis-fluoro-4-Methoxy-benzyl)-3-oxo-2,3- Dihydro-isoxazole-5-carbonyl]-amino }-2-hydroxy-butyric acid (tfa salt)
18. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(2-phenyl-azoles-5-carbonyl)-amino]-butanoic acid (tfa salt)
19. (2S, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(3H-[1,2,3] triazole-4-carbonyl)-amino]-butanoic acid (tfa salt)
20. (2R, 3R)-3-[(1-benzyl-1H-[1,2,3] triazole-4-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-2- Hydroxy-butyric acid (tfa salt)
21. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(1-hydroxyl-1H-[1,2,3] triazole-4-carbonyl)-ammonia Base]-butanoic acid (tfa salt)
22. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-{ [1-(the chloro-phenyl of 4-)-5-methyl isophthalic acid H-[1,2,4] triazole-3-carbonyl Base]-amino }-2-hydroxy-butyric acid (tfa salt)
23. (2R, 3R)-3-{ [1-(the fluoro-benzyl of the chloro-2-of 4-)-5-oxo-4,5-dihydro-1H-[1,2,4] triazole-3- Carbonyl]-amino }-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid (tfa salt)
24. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(5-oxa--3,3a-diaza-cyclopentano [a] naphthalene-2- Carbonyl)-amino]-butanoic acid (tfa salt)
25. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(5-oxa--3,3a-diaza-cyclopentano [a] naphthalene-2- Carbonyl)-amino]-ethyl n-butyrate. (tfa salt)
26. (2R, 3R)-4-(the chloro-phenyl of 2-)-3-[(4,5-dihydro-6-oxa--3,3a-diaza-benzo [e]-2- Carbonyl)-amino]-2-hydroxy-butyric acid (tfa salt)
27. (2S, 3R)-4-(the chloro-phenyl of 2-)-3-[(7-fluoro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxyl-fourth Acid (tfa salt)
28. (2S, 3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-2-hydroxyl-fourth Acid (tfa salt)
29. (2S, 3R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid (tfa salt)
30. (2S, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(7-methyl-3H-benzotriazole-5-carbonyl)-amino]- Butanoic acid (tfa salt)
31. 6-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-3H-benzo three Azoles-4-formic acid (tfa salt)
32. 5-[(1R, 2R)-2-carboxyl-1-(the chloro-benzyl of 2-)-2-hydroxy-ethyl carbamyl]-furan-2-first Acid (tfa salt)
33. (2R, 3R)-3-[(3-bromo-imidazo [1,2-a] pyridine-6-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-2- Hydroxy-butyric acid (tfa salt)
(34. 2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(5-hydroxyl-pyrazine-2-carbonyl)-amino]-butanoic acid (tfa salt)
35. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(2-hydroxy-pyrimidine-5-carbonyl)-amino]-butanoic acid (tfa salt)
36. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(3H-imidazo [4,5-b] pyridine-6-carbonyl)-ammonia Base]-butanoic acid (tfa salt)
N.d.=undetermined
37. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(1H-[1,2,3] triazol [4,5-b] pyridine-6-carbonyl Base)-amino]-butanoic acid (tfa salt)
38. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(1H-[1,2,3] triazol [4,5-b] pyridine-6-carbonyl Base)-amino]-ethyl n-butyrate. (tfa salt)
39. (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-carbonyl)- Amino]-butanoic acid
Preparation 4
(2R, 3R)-3-amino-2-hydroxyl-4-(2-trifluoromethyl-phenyl)-ethyl n-butyrate.
To (R)-2-amino-3-(2-trifluoromethyl-phenyl)-propanoic acid (25.0g, 107 μm ol) in water at 0 DEG C (230mL) suspension in is added dropwise over 4N NaOH aqueous solution (25mL).Then, N-(benzyloxy carbonyl oxygen is disposably added Base) succimide (26.8g, 107 μm ol) solution in acetone (100mL).Will mixing by adding 3N NaOH aqueous solution The pH value of thing maintains 8 to 9.Stirring mixture after 4 hours, is adjusted to 1 with 6N HCl by pH value, and with EtOAc (2 × 200mL) extraction mixture.The extract merged 1N HCl (2 × 200mL) washs, through anhydrous Na2SO4It is dried and concentrates, Compound (1) (35.0g) to white solid, shaped.
EDCI (20.0g, 104 μ is added in the compound (1) (35.0g, 95 μm ol) solution in DCM (300mL) Mol), HOBt (14.0g, 104 μm ol), N, O-dimethyl hydroxylamine hydrochloride (20.0g, 208 μm ol) and triethylamine (33.0g, 312μmol).It is stirred at room temperature mixture overnight.Then, mixture is respectively with 2N HCl (3 × 250mL) and NaHCO3Saturated Aqueous solution (3 × 200mL) washs.Organic layer is through anhydrous Na2SO4It is dried and concentrates, obtain compound (2) (35.0g).
To LiAlH at-20 DEG C4(3.3g, 85 μm ol) suspension in THF (300mL) is added dropwise over compound (2) (35.0g, the 85 μm ol) solution in THF (150mL).Mixture is stirred 2.5 hours at-20 DEG C.Then, reactant With 1N HCl cancellation carefully.Mixture EtOAc (2 × 300mL) extracts, and the extract merged is through anhydrous Na 2SO4It is dried And concentrate, obtaining compound (3) (29.8g), it the most directly uses without further purification.
NaHSO is added in the compound (3) (29.8g, 85 μm ol) solution in THF (250mL)3Aqueous solution (8.84g In 250mL water), and stir mixture overnight at 0 DEG C.Add NaCN (4.2g, 85 μm ol), and gained mixture is stirred 3 hours.Mixture EtOAc (2 × 300mL) extracts, and the extract merged is through anhydrous Na2SO4It is dried and concentrates, changed (32.1g, quantitatively), it the most directly uses compound (4) without further purification.
The compound (4) (32.1g, 85 μm ol) mixture in dioxane (200mL) and 6N HCl (200mL) is being returned Flow down heated overnight.Under reduced pressure remove solvent, and residue is dissolved in 3N HCl-EtOH solution.By gained mixture Solvent overnight and is under reduced pressure removed in backflow.Residue is dissolved in EtOAc (300mL) and NaHCO3In aqueous solution (300mL). Separate organic layer, through anhydrous Na2SO4It is dried and concentrates, obtain the mixture of title compound and its (R, S)-isomer, make institute State mixture and stand flash column chromatography (DCM:MeOH=100:1 to 50:1), obtain title compound (6.0g).
1H NMR(CDCl3): δ 7.68 (d, J=7.8Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 7.37 (m, 2H), 4.31 (m, 3H), 3.42 (m, 1H), 3.00 (dd, J=2.4,14.4Hz, 1H), 2.79 (m, 1H), 1.37 (t, J=7.1Hz, 3H).MS (m/z):292[M+H]+。
Preparation 5
1H-[1,2,3] triazol [4,5-b] pyridine-6-formic acid
By 6-amino-5-nitronicotinic acid methyl ester (5.0g, 25.4mmol, 1.0 equivalent) and acetic anhydride (100g) and sulphuric acid (1mL) merge.It is stirred at room temperature gained solution 2 hours.Solid by filtration is collected and uses 10%NaHCO3(aqueous solution) is washed Wash.Drying solid the most in an oven, obtains the compound (1) (3.9g) in yellow solid.
Compound (1) (3.9g, 16.3mmol, 1.0 equivalent) is dissolved in MeOH (200mL), and adds palladium carbon (0.5g).It is stirred at room temperature gained solutions overnight under hydrogen.Leach solid, and be concentrated under vacuum gained mixture, Compound (2) (3.0g) to white solid, shaped.
Compound (2) (3.0g, 14.4mmol, 1.0 equivalent) is dissolved in sulphuric acid/H2In O (1:4) (100mL).At 5 points At-5 DEG C to 0 DEG C, NaNO under agitation it is added dropwise in clock2(1.1g, 15.7mmol, 1.1 equivalent) molten in water (15mL) Liquid.In water ice is bathed, gained solution is stirred 1 hour at 0 DEG C.Solid by filtration is collected and is washed with water.Under reduced pressure exist Drying solid in baking oven, obtains the compound (3) (2.5g) in yellow solid.
Compound (3) (3.5g, 19.7mmol, 1.0 equivalent) is dissolved in THF (20mL).Addition NaOH (5.6g, 140.0mmol, 7.1 equivalents) solution in water (50mL), and it is stirred at room temperature gained solution 4 hours.Gained mixture exists Reduced under vacuum, then washs with EtOAc (2 × 30mL).With HCl (5mol/L), the pH value of solution is adjusted to 3.Solid passes through It is collected by filtration, and is dried the most in an oven, obtain the title compound (2.7g) of white solid, shaped.ES,m/z:165 [M+H]+；1HNMR(DMSO,300Hz,ppm)13.70(s,1H),9.19(s,1H),8.92(s,1H)。
Example 3
(2R, 3R)-2-hydroxyl-3-[(3H-[1,2,3] triazol [4,5-b] pyridine-6-carbonyl)-amino]-4-(2-tri- Methyl fluoride-phenyl)-butanoic acid
By 1H-[1,2,3] triazol [4,5-b] pyridine-6-formic acid (86mg, 520 μm mol, 1.0 equivalents) and HATU (239mg, 629 μm ol, 1.2 equivalents) are incorporated in DMF (3mL), and are stirred at room temperature 15 minutes.Add containing (2R, 3R)-3- The DIPEA of amino-2-hydroxyl-4-(2-trifluoromethyl-phenyl)-ethyl n-butyrate. (153mg, 524 μm ol, 1.0 equivalents) (182 μ L, 2.0 equivalents) and DMF (3mL), and it is stirred at room temperature gained mixture overnight.Add 2M NaOH aqueous solution (3mL) and THF (3mL) heating blends is overnight, and at 40 DEG C.Product passes through preparation HPLC purification, and obtain in tfa salt form is titled Compound (68.8mg, 100% purity).C17H14F3N5O4MS m/z [M+H]+Value of calculation: 410.10；Experiment value: 410.2.
Example 4
2-[6-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridazine-3-base]-benzoic acid (R 1 =-OH；R 41 =H)
By 6-chlorine pyridazine-3-formic acid (78.9mg, 497 μm ol, 1.0 equivalents), DIPEA (273 μ L, 3.2 equivalents), HATU (189mg, 497 μm ol, 1.0 equivalents) and (2R, 3R)-3-amino-2-hydroxy-4-phenyl-ethyl n-butyrate. (129mg, 497 μm ol, 1.0 equivalents) it is incorporated in DCM (2mL) and stirs 1 hour.Crude reaction thing uses gradient (0%-80%EtOAc/Hex) to carry out color Spectrum, obtains (2R, 3R)-3-[(6-chloro-pyridazine-3-carbonyl)-amino]-2-hydroxy-4-phenyl-ethyl n-butyrate..
By (2R, 3R)-3-[(6-chloro-pyridazine-3-carbonyl)-amino]-2-hydroxy-4-phenyl-ethyl n-butyrate. (172mg, 474 μm ol, 1.0 equivalents) mix with 2-tert-butoxycarbonyl phenyl-pinacol borate (173mg, 568 μm ol, 1.2 equivalents) In toluene (661 μ L).Sequentially add EtOH (361 μ L) and the predissolve K in water (124 μ L)2CO3(131mg, 947 μm ol, 2.0 equivalents).Stirring mixture, and reaction vessel is added a cover, put and under vacuo and purify with nitrogen.Add Pd (PPh3)4 (54.7mg, 47.4 μm ol).Container is added a cover again and heats 30 minutes at 100 DEG C.Remove organic layer, and steam under vacuo Send out product, obtain 2-[6-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3- Base]-t-butyl perbenzoate.
By 2-[6-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3- Base]-t-butyl perbenzoate (30mg, 59.3 μm ol) merges with TFA and DCM 1:1 (each 0.5mL), and gained mixture is stirred 30 minutes.Evaporation solvent, and product is dissolved in THF (0.5mL).Add 5M NaOH (0.3mL), and stir mixture mistake Night.Add AcOH with the pH value (about 1mL) being embodied as 5.Then, product passes through preparation HPLC purification, obtains title compound (1mg, 98% purity).C22H19N3O6MS m/z [M+H]+Value of calculation: 422.13；Experiment value: 422.
2-[6-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3-base]- Benzoic acid (R 1 =-OCH 2 CH 3 ；R 41 =H)
By 2-[6-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3- Base]-t-butyl perbenzoate (97.3mg, 192 μm ol) merges with TFA and DCM 1:1 (each 1mL), and gained mixture is stirred 1 Hour.Evaporation solvent, and add THF (3mL) and 1M NaOH aqueous solution (577 μ L, 3.0 equivalents).Stir the mixture for 2 hours, And add EtOAc.Extract water layer, and Organic substance NaOH (0.2mL) washs, stirring, and aqueous layer extracted, and add it to In first elution fraction.Aqueous solution concentrated hydrochloric acid is acidified to pH value and is about 5, forms colloidal solid.Remove aqueous solution, and solid is molten Solution, in AcOH and by preparation HPLC purification, obtains title compound (15mg, 97% purity).C24H23N3O6MS m/z [M+H]+Value of calculation: 450.16；Experiment value: 450.2.
2-[6-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3-base]- Ethyl benzoate (R 1 =-OCH 2 CH 3 ；R 41 =-CH 2 CH 3 )
By 6-chlorine pyridazine-3-formic acid (71mg, 440 μm ol, 1.0 equivalents), K2CO3(185mg, 1.3 μm ol, 3.0 equivalents) and 2-(4,4,5,5-tetramethyls-[1,3,2] dioxa boron penta ring-2-base)-ethyl benzoate (148mg, 535 μm ol, 1.2 equivalents) Merge with EtOH (1mL) and water (0.3mL).Stirring mixture, and reaction vessel is added a cover, it is placed under vacuum and clean with nitrogen Change.AddDPP-Pd (280 μm ol/g loads；286mg, 80.2 μm ol).Container is added a cover again and at 100 DEG C Lower microwave treatment 20 minutes.Remove solvent filtration product.With 1N HCl, pH value is adjusted to about 4.By HATU (136mg, 356 μ Mol, 0.8 equivalent), DIPEA (233 μ L, 3.0 equivalents) and (2R, 3R)-3-amino-2-hydroxy-4-phenyl-ethyl n-butyrate. (99.5mg, 446 μm ol, 1.0 equivalents) are incorporated in DCM (2mL) and stir 2 hours.Add AcOH, and product passes through preparative HPLC purification, obtains the title compound (1.8mg, 95% purity) in tfa salt form.C26H27N3O6MS m/z [M+H]+Meter Calculation value: 478.19；Experiment value: 478.
2-[6-((1R, 2R)-1-benzyl-2-butoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridazine-3-base]- Benzoic acid (R 1 =-O (CH 2 ) 3 CH 3 ；R 41 =H)
By (2R, 3R)-3-tertbutyloxycarbonylamino-2-hydroxy-4-phenyl-butanoic acid, (1.0 work as 70.9mg, 240 μm ol Amount) and n-butyl alcohol (2mL, 20mmol) be incorporated in the Isosorbide-5-Nitrae-dioxane (0.4mL, 2mmol) containing 4M HCl, and stir at 60 DEG C Mix 2 hours.Evaporation solvent, and make reactant mixture and toluene azeotropic.By 6-chlorine pyridazine-3-formic acid (38.1mg, 240 μm ol, 1.0 equivalents), DIPEA (134 μ L, 3.2 equivalents) and HATU (91.3mg, 240 μm ol, 1.0 equivalents) be incorporated in DCM (5mL), And it is stirred at room temperature 5 minutes.Then, this mixture is joined in the mixture of azeotropic, and stir 1 hour.Reactant Use saturated NH4Cl cancellation.Product extracted with DCM, is dried and evaporates, then passing through chromatograph (0%-60%EtOAc/ hexane gradient) Purification, obtains (2R, 3R)-3-[(6-chloro-pyridazine-3-carbonyl)-amino]-2-hydroxy-4-phenyl-butyl butyrate.
By (2R, 3R)-3-[(6-chloro-pyridazine-3-carbonyl)-amino]-2-hydroxy-4-phenyl-butyl butyrate (90mg, 230 μm ol, 1.0 equivalents) it is mixed in 2-tert-butoxycarbonyl phenyl-pinacol borate (83.8mg, 276 μm ol, 1.2 equivalents) In toluene (320 μ L).Sequentially add n-butyl alcohol (274 μ L) and the predissolve K in water (60 μ L)2CO3(63.5mg, 459 μ mol).Stirring mixture, and reaction vessel is added a cover, it is placed under vacuum and purifies with nitrogen.Add Pd (PPh3)4(26.5mg, 23μmol).Container is added a cover again and microwave treatment 40 minutes at 100 DEG C.Remove organic layer, add AcOH, and product leads to Cross preparation HPLC purification, obtain the title compound (41mg, 95% purity) in tfa salt form.C26H27N3O6MS m/z [M+H]+Value of calculation: 478.19；Experiment value: 478.2.
Example 5
Follow the program described in present example and replace suitable initial substance and reagent, with parent compound form or with The preparation of tfa salt form has a compound of Formulas I e:
1. (2R, 3R)-2-hydroxyl-3-[(4-oxo-1,2,3,3a, 4,5-hexahydro-pyrrolo-[1,2-a] quinoline quinoline-8- Carbonyl)-amino]-4-Phenyl-butyric acid
2. (2R, 3R)-3-{ [3-(6-bromo-pyridin-3-yl methyl)-7-methyl-2-propyl-3H-benzimidazole-5-carbonyl Base]-amino }-2-hydroxy-4-phenyl-butanoic acid (tfa salt)
3. (2R, 3R)-2-hydroxyl-3-[(7-methyl-2-propyl-3-pyridin-3-yl methyl-3H-benzimidazole-5-carbonyl Base)-amino]-4-Phenyl-butyric acid (tfa salt)
4. (2R, 3R)-2-hydroxyl-3-[(7-methyl-2-propyl-3-pyridin-3-yl methyl-3H-benzimidazole-5-carbonyl Base)-amino]-4-phenyl-butyric acid ethyl ester (tfa salt)
5. (2R, 3R)-3-[(3-carboxymethyl-7-methyl-2-propyl-3H-benzimidazole-5-carbonyl)-amino]-2-hydroxyl Base-4-Phenyl-butyric acid (tfa salt)
6. (2R, 3R)-2-hydroxyl-3-{ [3-(2-Methoxy-benzyl)-7-methyl-2-propyl-3H-benzimidazole-5- Carbonyl]-amino }-4-Phenyl-butyric acid (tfa salt)
7. (2R, 3R)-2-hydroxyl-3-{ [3-(4-Methoxy-benzyl)-7-methyl-2-propyl-3H-benzimidazole-5- Carbonyl]-amino }-4-Phenyl-butyric acid (tfa salt)
8. (2R, 3R)-3-[(3-carbamoyhnethyl-7-methyl-2-propyl-3H-benzimidazole-5-carbonyl)-amino]- 2-hydroxy-4-phenyl-butanoic acid (tfa salt)
9. (2R, 3R)-3-[(7-chloro-2-ethyl-3H-benzimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-fourth Acid
10. (2R, 3R)-3-[(7-chloro-2-ethyl-1H-benzimidazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-fourth Acetoacetic ester
11. (2R, 3R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butanoic acid (tfa salt)
12. (2R, 3R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-ethyl n-butyrate. (TFA Salt)
13. (2R, 3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butanoic acid
14. (2R, 3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-ethyl n-butyrate.
15. (2R, 3R)-2-hydroxyl-3-[(7-methyl-3H-benzotriazole-5-carbonyl)-amino]-4-Phenyl-butyric acid (tfa salt)
16. (2R, 3R)-3-[(7-fluoro-1H-benzotriazole-5-carbonyl)-amino]-2-hydroxy-4-phenyl-butanoic acid (TFA Salt)
17. (2S, 3R)-3-{ [the chloro-3-of 2-butyl-5-(3-hydroxyl-propyl)-3H-imidazoles-4-carbonyl]-amino }-2-hydroxyl Base-4-Phenyl-butyric acid (tfa salt)
18. 5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyrazine-2-formic acid (TFA Salt)
19. 2-[5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyrazine-2-base]-benzene Formic acid (tfa salt)
20. 5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridine-2-formic acid (TFA Salt)
21. 2-[5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridine-2-base]-benzene Formic acid (tfa salt)
22. 2-[4-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridine-2-base]-benzene Formic acid (tfa salt)
23. 2-[4-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridine-2- Base]-ethyl benzoate (tfa salt)
24. 2-[6-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridin-3-yl]-benzene Formic acid (tfa salt)
25. 2-[5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridin-3-yl]-benzene Formic acid (tfa salt)
26. 2-[2-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-pyridin-4-yl]-benzene Formic acid (tfa salt)
27. 2-[2-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridine-4- Base]-benzoic acid (tfa salt)
28. 2-[2-((1R, 2R)-1-benzyl-2-ethoxy carbonyl-2-hydroxy-ethyl carbamyl)-pyridine-4- Base]-ethyl benzoate (tfa salt)
29. (2R, 3R)-2-hydroxy-4-phenyl-3-[(1H-[1,2,3] triazol [4,5-b] pyridine-6-carbonyl)-ammonia Base]-butanoic acid (tfa salt)
30. (2R, 3R)-2-hydroxy-4-phenyl-3-[(pyrrolo-[1,2-c] pyrimidine-3-carbonyl)-amino]-butanoic acid (TFA Salt)
31. 5-((1R, 2R)-1-benzyl-2-carboxyl-2-hydroxy-ethyl carbamyl)-thiophene-2-carboxylic acid
Preparation 6
(R)-3-amino-4-(the chloro-phenyl of 2-)-ethyl n-butyrate.
(R)-3-amino-4-(the chloro-phenyl of 2-)-butanoic acid (10g, 50mmol) is dissolved in anhydrous EtOH (250mL).Add Enter concentrated hydrochloric acid (2mL), and heat the mixture to reflux overnight.Product vacuum is processed be dried and with toluene (4 × 50mL) Azeotropic, then puts the most overnight, obtains the title compound (10g) of white solid, shaped.
Example 6
2-{2-[(R)-1-carboxymethyl-2-(the chloro-phenyl of 2-)-ethyl carbamyl]-pyridin-4-yl }-benzoic acid
By 4-bromopyridine-2-formic acid (159mg, 788 μm ol, 1.0 equivalents), DIPEA (439 μ L, 3.2 equivalents) and HATU (300mg, 788 μm ol, 1.0 equivalents) are incorporated in DCM (20mL), and are stirred at room temperature 5 minutes.Addition (R)-3-amino- 4-(the chloro-phenyl of 2-)-ethyl n-butyrate. (200mg, 827 μm ol, 1.1 equivalents), and gained mixture is stirred 1 hour.Reactant Use saturated NH4Cl cancellation, then extracts with DCM, is dried and evaporates, obtaining thick intermedium.By K2CO3(163mg, 1.2mmol), 2-tert-butoxycarbonyl phenyl pinacol borate (264mg, 867 μm ol, 1.1 equivalents), EtOH (1mL) and water (0.3mL) add Enter in thick intermedium.Stirring mixture, and reaction vessel is added a cover, it is placed under vacuum and purifies with nitrogen.Add DPP-Pd (280 μm ol/g loads；563mg, 158 μm ol).Container is added a cover again and microwave treatment 30 minutes at 100 DEG C. Remove solvent filtration product.Add 1:1DCM:TFA, and gained mixture is stirred 2 hours at 40 DEG C.Evaporation solvent, and Crude product it is dissolved in AcOH (1.5mL) and by preparation HPLC purification, obtains the title compound in tfa salt form (50.0mg)。C23H19ClN2O5MS m/z [M+H]+Value of calculation: 439.10；Experiment value: 440.
Example 7
Follow the program described in present example and replace suitable initial substance and reagent, having with the preparation of tfa salt form The compound of Formulas I h:
1. (R)-4-(the chloro-phenyl of 2-)-3-[(3H-[1,2,3] triazole-4-carbonyl)-amino]-butanoic acid
2. (R)-4-(the chloro-phenyl of 2-)-3-[(7-methyl-3H-benzotriazole-5-carbonyl)-amino]-butanoic acid
3. (R)-3-[(3H-benzotriazole-5-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-butanoic acid
4. (R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-butanoic acid
N.d.=undetermined
5. (R)-3-[(1H-benzotriazole-5-carbonyl)-amino]-4-(the chloro-phenyl of 2-)-ethyl n-butyrate.
6. (R)-4-(the chloro-phenyl of 2-)-3-[(7-fluoro-1H-benzotriazole-5-carbonyl)-amino]-butanoic acid
7. (R)-4-(the chloro-phenyl of 2-)-3-[(1H-[1,2,3] triazol [4,5-b] pyridine-6-carbonyl)-amino]-fourth Acid
8. (R)-4-(the chloro-phenyl of 2-)-3-[(2-hydroxy-pyrimidine-5-carbonyl)-amino]-butanoic acid
-XR4R5R6=
9. 2-{6-[(R)-2-carboxyl-1-(the chloro-benzyl of 2-)-ethyl carbamyl]-pyridazine-3-base }-benzoic acid
Analyze 1
The quantitatively analyzed in vitro of the usefulness of inhibitor on human class and rat NEP and mankind ACE
Analyzed in vitro as described below is used to measure compound to the mankind and rat enkephalinase (EC 3.4.24.11； And the inhibitory activity of human blood angiotonin invertase (ACE) NEP).
NEP activity is extracted from rat kidney
Rat NEP is prepared by the kidney carrying out (Sprague Dawley) rat from adult Sprague road.Complete kidney in Washing in cold phosphate buffered saline (PBS) (PBS), and with the ratio of 5 milliliters of buffer of every gram of kidney in ice-cold lysis buffer (1% Triton X-114,150mM NaCl, 50mM tri-(methylol) aminomethane (Tris), pH 7.5；Bordie (Bordier) (1981) journal of biological chemistry 256:1604-1607) middle process.Polytron hand held tissue dismembyator is used to make sample on ice Originally homogenize.Tissue homogenate is centrifuged 5 minutes with 1000 × g at 3 DEG C in swinging bucket rotor.Centrifugal-block is resuspended in 20mL ice Hatch in cold cut solution buffer and on ice 30 minutes.Sample (15mL to 20mL) following layer is laid on 25mL ice-cold bed course buffer On (cushion buffer) (6%w/v sucrose, 50mM pH 7.5Tris, 150mM NaCl, 0.06%Triton X-114), Continue 3 to 5 minutes after being heated to 37 DEG C, and at room temperature in swinging bucket rotor, be centrifuged 3 minutes with 1000 × g.In sucking-off two Layer, leaves the sticky oil precipitate containing enrichment film part.Addition glycerol is stored in-20 DEG C to concentration and the sample of 50% Under.Use BCA detecting system, using bovine serum albumin (BSA) as reference material quantifying protein concentration.
Enzyme level is analyzed
Recombinant human NEP and recombinant human ACE is (the R&D system house of Minneapolis, Minnesota buied (R&D Systems, Minneapolis, MN), catalog number (Cat.No.) is respectively 1182-ZN and 929-ZN).Fluorescent peptide substrate Mca-D- Arg-Arg-Leu-Dap-(Dnp)-OH (Medeiros (Medeiros) et al. (1997) Brazil's medical science and biological study magazine (Braz.J.Med.Biol.Res.)30:1157-62；Peace Spike company (Anaspec, the San of San Jose Jose, CA)) and Abz-Phe-Arg-Lys (Dnp)-Pro-OH (A Laoyue (Araujo) et al. (2000) biochemistry (Biochemistry)39:8519-8525；The Ba Heng company (Bachem, Torrance, CA) of Torrance, California) It is respectively used in NEP and ACE analysis.
Analysis be use fluorescent peptide substrate under the concentration of 10 μMs in analysis buffer (NEP:50mM HEPES (pH7.5), 100mM NaCl, 0.01% Polyethylene Glycol sorbitan monolaurate (Tween-20), 10 μMs of ZnSO4；ACE:50mM HEPES (pH 7.5), 100mM NaCl, 0.01%Tween-20,1 μM of ZnSO4At 384 hole White-opalescents at 37 DEG C in) Plate is carried out.The concentration of enzyme out of the ordinary should make 1 μM of substrate that Quantitative Western hydrolysis occurs after 20 minutes at 37 DEG C.
In 10 μMs to the concentration range of 20pM, test compound is analyzed.Will test compound add in enzyme and Hatch at 37 DEG C 30 minutes, make reaction start by addition substrate subsequently.By adding after hatching at 37 DEG C 20 minutes Glacial acetic acid is that 3.6% (v/v) terminates reaction to ultimate density.
It is respectively set as in the exometer of 320nm and 405nm reading plate exciting and launching wavelength.Inhibition constant is to pass through Use below equation that data carry out nonlinear regression (San Diego, California chart board software company (GraphPad Software, Inc., San Diego, CA)) and obtain:
V=v0/[1+(I/K')]
Wherein v is reaction rate, v0For the reaction rate not suppressed, I is inhibitor concentration and K' is apparent inhibition constant.
Test the compounds of this invention in the analysis and find that it has following pK to mankind NEPiValue.In general, front Drug compound not inhibitory enzyme in this analyzed in vitro, or prodrug do not tests (n.d.) because expection is the most active.
Analyze 2
In anesthetized rat, the pharmacodynamics (PD) of ACE and NEP activity is analyzed
Male Sprague road is made to carry out normal blood pressure rats fiber crops with 120mg/kg (intraperitoneal) Inactin (inactin) Liquor-saturated.After being anesthetized, insert jugular vein, carotid artery (PE 50 manages) and bladder (enlarging PE 50 manages) conduit and carry out tracheotomy (Teflon pin (Teflon Needle), No. 14 size) is to promote spontaneous respiration.Then the period that animal stablizes 60 minutes is made And keep continuous infusion 5mL/kg/h saline (0.9%) during whole, so that it keeps aqueous and guarantees to produce urine.? By using heating cushion to maintain body temperature during whole experiment.At the end of 60 minutes stable phases, it is separated by 15 minutes intravenouss (i.v.) two doses of AngI of animal (1.0 μ g/kg, for ACE inhibitor activity) are given.After second dose of AngI 15 minutes, use matchmaker Agent or test compound treated animals.After 5 minutes, animal is additionally with rapid intravenous injection atrial natriuretic peptide (ANP；30μg/ Kg) treated.After ANP treats, at once start to collect urine (insert preweighted Eppendorf tube (eppendorf Tube) in) and continue 60 minutes.When urine is collected 30 minutes and 60 minutes, animal AngI excites again.Use promise spy's Coudé (Notocord) system (state of Michigan Kalamazoo (Kalamazoo, MI)) carries out blood pressure measurement.Urine sample is cold at-20 DEG C Freeze until analyzing for cGMP.By using the commercial kit (analysis Chevron Research Company (CRC) (Assay of Ann Arbor, Michigan Designs, Ann Arbor, Michigan), catalog number (Cat.No.) 901-013) carry out EIA enzyme immunoassay measure urine cGMP concentration.With weight Component analysis mode measures urine volume.Urine cGMP output is calculated as the product urinating output with urine cGMP concentration.ACE suppression is logical Cross and quantitatively the suppression % of the booster reaction of AngI is assessed.NEP suppression is the urine cGMP output induced by quantitative ANP The enhancing raised is assessed.
Analyze 3
The internal assessment of antihypertensive function in sentient hypertension SHR model
Spontaneous hypertension rat (SHR, 14 to 20 week old) is made to adapt to environment minimum 48 hours after sending to testing location, its In can freely obtain food and water.For recording blood pressure, with operation by Small rodents radio transmitter (remote unit； DSI model TA11PA-C40 or C50-PXT, U.S. Data scientific company (Data Science Inc., USA)) implant these and move In thing.It is positioned at the descending aorta (descending above common iliac artery crotch by inserting with the catheter tip that transmitter is connected Aorta) in and the most fixing with tissue adhesion agent.Transmitter is maintained at intraperitoneal and is fixed on stomach wall, simultaneously with inhaling Receive suture abdominal incision.External skin stitching thread and suturing nail are sewed up.Animal is made to recover with the most postoperative looking after.? Experimental day, the top that animal in cage is seated in telemetry receiver unit with adaptive testing environment and carries out baseline record.? After carrying out base line measurement at least 2 hours, then to animal come into operation mediator or test compound and perform be administered latter 24 hours blood Pressure is measured.Use promise spy's Coudé software (state of Michigan Kalamazoo) continuously record data and save as electron number during studying Word signal.The parameter measured is blood pressure (shrinking pressure, diastolic pressure and mean arterial pressure) and heart rate.
Analyze 4
The internal assessment of antihypertensive function in sentient hypertension DOCA-salt rat model
CD rat (male, grow up, 200 grams to 300 grams, U.S.'s Charles River Laboratories (Charles River Laboratory, USA)) one send to testing location and i.e. adapt to environment minimum 48 hours, it is seated in subsequently on high salt meals. After high salt meals (8% in food or 1%NaCl is in drinking water) start 1 week, it is subcutaneously implanted deoxy-corticosterone acetate (DOCA) pill (100mg, 90 day release time, innovation research company of the U.S. (Innovative of Florida State Sarasota Research of America, Sarasota, FL)) and carry out unilateral nephrectomy.Now, also with operation, small-sized grinding tooth is moved Thing radio transmitter is implanted in animal to measure blood pressure (referring to analyze 3).Animal is made to recover with the most postoperative looking after.Research sets The parameter of meter, data record and measurement is similar to for analyzing person described in 3.
Analyze 5
The internal assessment of antihypertensive function in sentient hypertension Dahl/SS rat model
Male Dahl salt-sensitive rat (Dahl/SS, 6 to 7 week old, from U.S.'s Charles River Laboratories) one is sent to survey Examination place i.e. adapts to environment at least 48 hours, and (TD.92012, orchid breathes out in the U.S. to be seated in 8%NaCl high salt meals subsequently (Harlan, USA)) on, then (refer to analyze to measure blood pressure by the implantation of Small rodents radio transmitter with operation 3).Animal is made to recover with the most postoperative looking after.About 4 to 5 week after high salt meals start, it is contemplated that these animals become have height Blood pressure.Once confirming High blood pressure levels, these animals are i.e. used for studying, and continue high salt meals to maintain its hypertension water simultaneously Flat.The parameter of research design, data record and measurement is similar to analyze person described in 3.
Although the present invention is been described by with reference to its particular aspects or embodiment, but it will be understood by one of ordinary skill in the art that Can make various changes in the case of without departing from true spirit and scope of the present invention or replaceable equivalent.It addition, be suitable for In the range of decree on patent and regulation allow, herein cited all publication, patents and patent applications case are quoted the most in full Mode be incorporated herein, described in the degree quoted the most individually be incorporated herein by reference one just as each document As.

Claims (16)

1. a compound of formula I,
Wherein:
R1For-OR10；R10For H or-C1-6Alkyl；
R2For H or-OR20；R20For H；
R3Selected from H, Cl and-CF3；
X is selected from furan, thiophene, imidazoles, triazole, azoles, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzo three Azoles, Triazolopyridine, imidazopyridine, pyrrolopyrimidine, 5-oxa--3,3a-diaza cyclopentano [a] naphthalene, dihydro triazole, two Hydrogen isoxazole, tetrahydro pyridazine, hexahydropyrrolo quinoxaline and dihydro oxa-diaza benzo [e]；
R4Selected from H；Halogen；-C0-5Alkylidene-OH；-C1-6Alkyl；-C0-1Alkylidene-C (O) OR41；=O；Optionally through a halogen Substituted phenyl；With when X is pyridazine, pyrazine or pyridine, through-C (O) OR41Substituted phenyl；R41For H or-C1-6Alkyl；
R5Do not exist or selected from H；-C0-3Alkylidene-OH；-C1-3Alkylidene-C (O) OR50；-CH2-C(O)NR51R52；Optionally through halogen Substituted-the C of base0-2Alkylene-pyridine；
R50For H；R51And R52For H；R53Selected from H, halogen and-O-C1-6Alkyl；R54For H or halogen；R55Selected from H, halogen and-O- C1-6Alkyl；R56For H；And R57For H；And R6Do not exist or selected from H, halogen ,-OH and-C1-6Alkyl；
Or its pharmaceutically acceptable salt.
Compound the most according to claim 1, wherein:
R2For-OR20；R20For H；
R3For Cl；
X selected from furan, triazole, azoles, isoxazole, pyridine, pyrazine, pyrimidine, benzotriazole, Triazolopyridine, imidazopyridine, 5-oxa--3,3a-diaza cyclopentano [a] naphthalene, tetrahydro pyridazine and dihydro oxa-diaza benzo [e]；
R4Selected from H；Halogen；-C0-5Alkylidene-OH；-C1-6Alkyl；-C0-1Alkylidene-C (O) OR41；=O；Optionally through a halogen Substituted phenyl, and when X is pyrazine or pyridine, through-C (O) OR41Substituted phenyl；R41It is selected from H and-C1-6Alkyl；
R5Do not exist or selected from H ,-C0-3Alkylidene-OH,
R53For H or halogen；R54For H or halogen；R55Selected from H, halogen and-O-C1-6Alkyl；R56For H；R57For H；And R6Do not exist Or selected from H, halogen ,-OH and-C1-6Alkyl.
Compound the most according to claim 1, wherein:
R2For-OR20；R20For H；
R3For-CF3；
X is Triazolopyridine；
R4For H；
R5For H；And
R6For H.
Compound the most according to claim 1, wherein:
R2For-OR20；R20For H；
R3For H；
X is selected from thiophene, imidazoles, pyridine, pyrazine, pyridazine, benzimidazole, benzotriazole, Triazolopyridine, pyrrolopyrimidine and six Hydrogen pyrrolo-quinoxaline；
R4Selected from H；Halogen；-C1-6Alkyl；-C0-1Alkylidene-C (O) OR41；=O；With when X is pyridazine, pyrazine or pyridine, through- C(O)OR41Substituted phenyl；R41For H or-C1-6Alkyl；
R5Do not exist or selected from H；-C0-3Alkylidene-OH；-C1-3Alkylidene-C (O) OR50；-CH2-C(O)NR51R52；Optionally through halogen Substituted-the C of base0-2Alkylene-pyridine；
With
R50For H；R51And R52For H；R53For H or-O-C1-6Alkyl；R54For H；R55For H or-O-C1-6Alkyl；R56For H；R57For H； And R6Do not exist or selected from H and halogen.
Compound the most according to claim 1, wherein:
R2For H；
R3For Cl；
X is selected from triazole, pyridine, pyrimidine, pyridazine, benzotriazole and Triazolopyridine；
R4Selected from H, halogen ,-C0-5Alkylidene-OH ,-C1-6Alkyl and when X is pyridazine or pyridine through-C (O) OR41Substituted benzene Base；R41For H；
R5Do not exist or for H；And
R6Do not exist or for H.
Compound the most according to claim 1, its be (2R, 3R)-4-(the chloro-phenyl of 2-)-2-hydroxyl-3-[(3-hydroxyl- Isoxazole-5-carbonyl)-amino]-butanoic acid.
Compound the most according to claim 1, it is (2S, 3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-ammonia Base]-4-(the chloro-phenyl of 2-)-2-hydroxy-butyric acid.
Compound the most according to claim 1, it is (R)-4-(the chloro-phenyl of 2-)-3-[(2-hydroxy-pyrimidine-5-carbonyl Base)-amino]-butanoic acid.
9. a medical composition, it comprises according to the compound described in any one in claim 1-5 and pharmaceutically may be used Accept supporting agent.
Medical composition the most according to claim 9, it additionally comprises selected from following therapeutic agent: adenosine receptor antagonist Agent, alpha-adrenergic aceptor antagonist, β1-adrenergic aceptor antagonist, β2-3 adrenergic receptor agonists, dual Functionality B-adrenergic receptor antagonist/α1-receptor antagonist, Advanced glycation endproducts decomposition agent, aldosterone are short of money Anti-agent, aldosterone synthase inhibitor, aminopeptidase N inhibitor, androgen, angiotensin-convertion enzyme inhibitor, dual work With property angiotensin converting enzyme/enkephalinase inhibitor, angiotensin converting enzyme 2 stimulant, Angiotensin II vaccine, Anticoagulant, anti-diabetic medicament, antidiarrheal, glaucoma medicament, lipotropism matter medicament, Pain relief agents, antithrombotic agent, AT1 Receptor antagonist, dual function AT1Receptor antagonist/enkephalinase inhibitor, multi-functional angiotensin receptor blocker, Bradykinin receptor antagonists, calcium channel blocker, chymase inhibitor, digoxin, diuretic, dopamine agonist, Endothelin turn Change enzyme inhibitor, endothelin-receptor antagonists, HMG-CoA reductase inhibitor, estrogen, estrogen receptor agonist and/or Antagonist, monoamine re-uptake inhibitor, muscle relaxant, natriuretic peptide, natriuretic peptide remove receptor antagonist, enkephalinase suppression Agent, nitric oxide donors, non-steroid anti-inflammatory agent, N-methyl d-aspartate receptor agonist, opioid agonist Agent, phosphodiesterase inhibitor, prostanoid, Prostanoid receptor agonist, renin inhibitor, selective serotonin are taken the photograph again Take inhibitor, sodium channel blockers, sGC stimulant, tricyclic antidepressants, vasopressin receptor short of money Anti-agent, and a combination thereof.
11. medical compositions according to claim 9, it additionally comprises selected from following therapeutic agent: angiotensin turns Change enzyme 2 activator and soluble guanylate cyclase activators.
12. medical compositions according to claim 10, wherein said therapeutic agent is AT1Receptor antagonist.
13. 1 kinds of methods prepared according to the compound described in any one in claim 1-5, it comprises the steps of
A () makes compound 1 and compound 2 coupling:
B () makes compound 1 and compound 2a coupling to form compound 3:
Wherein L is leaving group, and makes compound 3 and through substituted 4,4,5,5-tetramethyl-2-phenyl-[1,3,2] the dioxy boron of R Pentane:
Reacting in the coupling reaction of palladium chtalyst, wherein R is halogen, or when X is pyridazine, pyrazine or pyridine, R is-C (O) OR41, and R41For H or-C1-6Alkyl；Or
C () makes compound 2b react with through R substituted 4,4,5,5-tetramethyl-2-phenyl-[1,3,2] dioxy boron pentane with at palladium Formation compound 4 in the coupling reaction of catalysis:
Wherein L is leaving group, and P1For selected from methyl, ethyl, the tert-butyl group, benzyl, to mehtoxybenzyl, 9-fluorenyl methyl, The carboxyl-protecting group of TMS, t-butyldimethylsilyi and benzhydryl, and make compound 4 even with compound 1 Closing, wherein R is halogen, or when X is pyridazine, pyrazine or pyridine, R is-C (O) OR41, and R41For H or-C1-6Alkyl；With And
(d) optionally make the product removal protection group of step (a) or (b) or (c) with compound of formula I or its pharmaceutically may be used The salt accepted.
14. methods according to claim 13, wherein said leaving group is halogen.
15. 1 kinds of intermediums, it is be applicable to synthesis according to the compound described in any one claim 1-5, and it has formula II:
Wherein P is-O-P1；And P1For selected from methyl, ethyl, the tert-butyl group, benzyl, to mehtoxybenzyl, 9-fluorenyl methyl, The carboxyl-protecting group of TMS, t-butyldimethylsilyi and benzhydryl, or its salt.
16. 1 kinds of purposes according to the compound described in any one in claim 1-5, it is for manufacturing for treating high blood Pressure, heart failure or the medicament of nephropathy.
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